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ADCs

ONCOLOGY

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INNOVATION FOR QUALITY, COST& COMPETITIVE ADVANTAGE P30

I N N O V A T I O N F E A T U R E

CRB Segregation in the Design of Gene Therapy Manufacturing Facilities p16

MARKENManaging the Complexities of Outbound Clinical Drug Distribution p10

GE HEALTHCARESingle-Use Operational Excellence Explained: Effective Lifecycle Management p46

ICAGENDeveloping Targeted Potassium Channel Openers for CNS-Related Therapeutics p38

GLOBAL PHARMACEUTICAL SUPPLY CHAIN TRENDS

THE ROLE OF INNOVATIVE TECHNOLOGIES

Q4 2017 EDITION

ONCOLOGY

GCTA

PHARMASALMANAC.COM 3

> TABLE OF CONTENTS Pharma’s Almanac

GLOBAL PHARMACEUTICAL SUPPLY CHAIN TRENDS Q4 2017 EDITION

04 A Note from the Editor Emilie Branch, Nice Insight

06 Nice Insight Overview: From Digitalization to Nanoscale Delivery: Emerging Technologies Are Driving the Future of Pharma

Nigel Walker, That’s Nice LLC/Nice Insight

10 Industry Leader Insight: Managing the Complexities of Outbound Clinical Drug Distribution

Wes Wheeler and Ariette van Strien, Marken

16 Segregation in the Design of Gene Therapy Manufacturing Facilities

Peter Walters, CRB USA

19 Dashboard: Membership Levels Provide Insight to Your Most Interested Viewers

Nice Insight

20 Virtual Panel: ADCs: The Future of Biologic Drugs

Guy Tiene, Nice Insight

26 Right-First-Time Innovation Approach Drives Continual Investment

Adam Kujath, Alcami Corporation

38 Developing Targeted Potassium Channel Openers for CNS-Related Therapeutics

Douglas Krafte, Ph.D., Neil Castle, Ph.D. and Aaron Gerlach, Ph.D., Icagen, Inc.

42 Achieving Efficient Pharmaceutical Synthesis with Process Intensification

Stéphane Laurent, Servier CDMO

46 Single-Use Operational Excellence Explained: Effective Lifecycle Management

Ken Clapp, GE Healthcare

50 Company Profiles Nice Insight

51 Content and Research Web Platform Guy Tiene, Nice Insight

52 Roundtable: Innovative Technologies Nice Insight

GSK leverages its resources and expertise as one of the world’s premier science-led global healthcare companies in providing contract manufacturing services to companies seeking to outsource development and manufacturing of biopharmaceutical products.

GSK Biopharmaceuticals Email: [email protected] www.gsk.com/biopharm

Biopharmaceutical Contract Manufacturing

GSKR_PA_Q4_2017.indd 1 10/17/17 8:47 AM

With over 1,000 pages published in just one year, Pharma’s Almanac is now online.www.PharmasAlmanac.com

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Gain exposure with your own thought leadership in a future Pharma’s Almanac. Call Guy Tiene at +1 212 366 4455 or email [email protected]

PAGE 30

INNO

VATI

ON F

EATU

RECynthia Challener, Ph.D., Steve Kuehn and Emilie Branch

INNOVATION FOR QUALITY, COST & COMPETITIVE ADVANTAGE

> A NOTE FROM THE EDITOR

Q4 2 0 1 7 VOLU M E 3 NU M BER 4

N ICE IN SIGH T LLC/TH AT’S NICE 89 Fifth Avenue – 5th Floor – NY 10003 – USA Telephone: + 1 212 366 4455

New York – Raleigh – Chicago – San Diego Santa Monica – San Francisco – London Frankfurt – Shanghai – Shenzhen

WWW.N ICEINSIGH T.COM

P UB L IS HING M ANAGING D IRECTOR Nigel Walker | [email protected]

S T RAT EGIC CONTENT D IRECTOR Guy Tiene | [email protected]

E XECUT IVE CONTENT D IRECTOR Steve Kuehn | [email protected]

S CI EN T IFIC CONTENT D IRECTOR Cynthia Challener, Ph.D. | [email protected]

S T RAT EGIC CONTENT M ANAGER Emilie Branch | [email protected]

S CI EN T IFIC CONTRIBU TORS Carrie Cao, Ph.D. | [email protected] David Torrone | [email protected]

S CI EN T IFIC RESEARCH M ANAGERS Kshitij Ladage | [email protected] Govindra Singh | [email protected]

S CI EN T IFIC RESEARCH ASSOCIATES Saakshi Gupta | [email protected] Maurice Spicer | [email protected]

P UB L IS HING ACCOU NT D IRECTOR Wei Gao | [email protected]

P UB L IS HING D ESIGN D IRECTOR Young Tae | [email protected]

P UB L IS HING D ESIGN TEAM Erin Carney | [email protected] Chee Choi | [email protected] Mikhail Iliatov | [email protected]

B I OT ECH CONTENT CONTRIBUTOR Graham Combe | [email protected]

Nice Insight is the market research division of That’s Nice LLC, A Science Agency, leading marketing in the life sciences.

Pharma’s Almanac is printed quarterly and distributed as a supplement to Pharmaceutical Outsourcing (PO) 20,000 BPA-audited readers throughout North America to senior executives, scientists and others seeking outsourced services. Additionally, content is promoted via the PO newsletter to 12,024 readers. All content is also promoted via the Pharma’s Almanac newsletter to 65,000 non-BPA audited recipients. With print copies and digital promotion, each issue reaches over 100,000 industry professionals. All content can be found on www.PharmasAlmanac.com.

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www.PharmasAlmanac.com

nnovation is at the heart of the phar-

maceutical industry. Ongoing inno-

vation is essential for advancement

of pharmaceutical science and man-

ufacturing. From advances in robotics for

rapid, high-throughput analytics to the en-

hancement of crystallization and imaging

technologies for the construction of more

accurate models of biochemical reactions,

to the development of robust single-use

systems for continuous chromatography —

all have required creative thinking and the

application of existing knowledge in pro-

foundly new ways.

Enhancing the safety of manufactur-

ing processes and the development of

high-quality medications under constantly

evolving market conditions also requires

continual innovation across all activities

in the pharmaceutical industry. Innovative

regulatory approaches can, for instance,

drive efficient, cost-effective and acceler-

ated commercialization of therapies as ef-

fectively as modeling techniques and mod-

ernized equipment.

Although the pharmaceutical industry is

currently challenged to reduce costs and

improve efficiencies, manufacturers con-

tinue to invest in discovery efforts that are

uncovering next-generation medicines to

address truly unmet medical needs. Gene

and cell-based therapies are moving us

closer to personalized medicines than ever

before. Advances in management systems

for clinical trial material distribution are

making it possible to conduct clinical trials

in any location — from patient homes and

investigator sites.

Up-to-date structural data high-through-

put screening techniques are enhancing our

understanding of potential drug targets and

speeding up the discovery of more effec-

tive candidate therapeutics, from ion chan-

nel modulators to bispecific antibodies

and next-generation antibody-drug conju-

gates. New platform approaches to both

drug discovery and manufacturing are

reducing the cost and time for drug de-

velopment and manufacturing. Additive

manufacturing and nanoparticulate drug

delivery systems are creating entirely

new formulating and delivery opportuni-

ties. Process intensification of small and

large molecule manufacturing is provid-

ing opportunities to develop optimum

processes that are readily scalable and

often more cost effective than traditional

batch solutions.

Change often proceeds at a slow pace

in the pharmaceutical industry given the

potential for significant consequences. It

does occur, however. And today innovation

is alive and well — and increasingly support-

ed by regulatory agencies and governments

looking to accelerate the development of

safe, affordable, effective medicines. Inno-

vative medicines may not just be the cure,

but treat diseases once thought untreat-

able. Updated manufacturing technolo-

gies may facilitate the development of in-

creasingly efficient processes that provide

higher-quality products, more consistently.

Innovation is clearly driving a bright future

for pharma — in spite of, and in part driven

by, the challenges facing the sector. P

INNOVATION: DRIVING PHARMA’S BRIGHT FUTURE

BY EMILIE BRANCH., NICE INSIGHT>

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Innovation Is EssentialManufacturing and quality issues have been

at the heart of many drug recalls and short-

ages, which have a huge negative impact on

the pharma industry’s ultimate customer — the patient. While state-of-the-art technolo-

gies are often employed in pharmaceutical

discovery efforts, they are not regularly imple-

mented on the plant floor. Traditional manu-

facturing approaches are, however, clearly

no longer sufficient to meet the challenges

posed by today’s complex drug substances

and formulated products. Changes occurring

in the pharmaceutical industry are also driv-

ing the need for a move away from traditional

manufacturing practices to new manufactur-

ing platforms and technologies that will allow

accelerated development and production.

Some of these changes will be incremental

innovations that modernize existing systems.

Others will involve the introduction and imple-

mentation of novel technologies and opera-

tional methodologies. Most pharmaceutical

companies recognize the need for innovation

and are actively pursuing the implementation

of advanced technologies and solutions, such

as continuous process and single-use systems.

NICE INSIGHT OVERVIEW

6 PHARMA’S ALMANAC GLOBAL PHARMACEUTICAL SUPPLY CHAIN TRENDS Q4 2017

New Approach from FDAOne of the biggest hindrances to adoption of

emerging technologies in the pharmaceutical

industry is concern over regulatory agency

acceptance. Realizing the crucial need for

modern manufacturing technologies and their

potential to improve the robustness, flexibility

and quality of pharmaceutical production pro-

cesses, FDA’s Office of Pharmaceutical Quality

(OPQ) within the Center for Drug Evaluation

and Research (CDER) “is determined that regu-

latory agility is warranted to facilitate — and

not hinder — company efforts to adopt novel

or otherwise unfamiliar technologies.”1 OPQ

established the Emerging Technology Program

(ETP), which is run by the Emerging Technology

Team (ETT) and published draft guidance for

industry — Advancement of Emerging Technol-

ogy Applications to Modernize the Pharmaceu-

tical Manufacturing Base.

Companies making regulatory submissions,

including investigational new drug applica-

tions (IND), original or supplemental new drug

applications (NDA), abbreviated new drug

applications (ANDA) or biologic license appli-

cations (BLA), or application-associated Drug

he (bio)pharmaceutical industry is becoming a high-technology sector with success directly linked to innovation. There is a cautious adoption of new technologies given the potential impacts on patient

health, but it is occurring. The latest technologies shaping the future of the industry range from cloud computing to additive manufacturing to nanoparticulates, and of course continuous manufacturing and single-use systems.

FROM DIGITALIZATION TONANOSCALE DELIVERY: Emerging Technologies Are Driving the Future of Pharma

BY NIGEL WALKER, THAT’S NICE LLC / NICE INSIGHT

organs, the synthesis of small molecule

APIs and the formulation of solid-dosage

drugs.8 The technology is at the early

stages for these applications, however,

and much more work must still be done.

“Printing technologies will be able to

become manufacturing tools of the future

if the capabilities of the printers are con-

tinuously developed. This also means that

a wider range of printable materials has to

be developed to broaden the possibilities

to create multifunctional drug delivery

systems and medical devices,” according

to a blog posted by the American Associa-

tion of Pharmaceutical Scientists.9

A Look at Nanotech in PharmaThere is significant potential for nano-

technology to be applied in the pharma-

ceutical industry, from smart materials

for tissue engineering to intelligent tools

for drug delivery. Grand View Research

estimates that the global nanomedicine

market is growing at a compound annual

growth rate of 11.2%, and will be valued at

$350.8 billion by 2025.12

8 PHARMA’S ALMANAC GLOBAL PHARMACEUTICAL SUPPLY CHAIN TRENDS Q4 2017 PHARMASALMANAC.COM 9

2. Gamification of health to incentivize patients and medical professionals to use their products, which will require the utilization of advanced digital gaming technologies.

3. Augmented and virtual realities and associated devices are creating a new view of the world that pharma companies can leverage to create impactful experiences for patients, caregivers and physicians.

4. Widespread, cost-effective genome sequencing for personalized medicine, which will change the way drugs are prescribed.

5. Body sensors for data collection inside and outside of the body will provide much more detailed data about patients in clinical trials and who receive approved medicines. If properly leveraged this can be used to develop more effective drugs.

6. ‘Do it yourself’ biotechnology — think of the inexpensive test for pancreatic cancer developed by a 15-year-old — which if sup-ported effectively by the industry could lead to key innovations that still remain safe and compliant.

7. Additive manufacturing, which is already used for the production of medical implants, could be used to manufacture pharmaceutical equipment and even drug substances. In fact, FDA approved a 3D-printed drug (Aprecia’s Spritam (levetiracetam) tablets for oral suspension for treatment of seizures in adults and children with certain types of epilepsy) in August 2015.4 Someday it may be possible for pharmacies or even patients to print customized medicines, eliminating the need for big pharma manufacturing.

8. Elimination of human clinical trials through the use of simulations of human physiology.

9. The use of supercomputers and artificial intelligence (AI) to make complex deci-sions and dramatically facilitate pharma-ceutical research.

10. Nanotechnology applied to medi-cine, such as the use of nanorobots in blood for early diseases diagnosis and nanoscale drugs for targeted delivery.

David Epstein, an Executive Partner at

Flagship Pioneering and Chairman of

the Board of Rubius Therapeutics, noted

in a March 2017 interview with Martin

Dewhurst, a Senior Partner in McKin-

sey’s London office, that cellular thera-

pies, improved diagnostic tests based on

whole-genome screening and new ways of

performing remote patient monitoring in

the home were beginning to impact the

industry.5 He also observed that there

is enormous waste in current health

practices that digital solutions should

address, noting: “There are some incred-

ible innovations out there — technology

that enables a different level of efficiency,

joined-up thinking within patient care.”5

Spotlight on Additive ManufacturingIn light of its consideration of 3D printing

as an important emerging technology, FDA

issued draft guidance on the use of addi-

tive manufacturing for drug and device

production in May 2016.6 In an August

2016 interview with Pharmaceutical Tech-

nology magazine, Kristofer Baumgartner,

a spokesperson for CDER, indicated that

existing approval pathways are “flex-

ible enough to address new technologies,

small batches, orphan/expedited review,

and personalized medicines,”7 including

those involving 3D printing.

Features of 3D printing — portable

equipment, the ability to produce cus-

tomized final dosage forms with multiple

ingredients, perhaps in multi-layered

tablets — make the technology ideal

for personalized medicines.7 CDER/

OPQ’s Office of Testing and Research’s

Division of Product Quality Research

has established a manufacturing sci-

ence research program with the goal

of enabling innovation and advancing

the understanding of the risks and ben-

efits of novel technologies, including 3D

printing, according to Baumgartner.7

Several academic groups are investigat-

ing the use of additive manufacturing for

the production of living cells, tissues and

Master Files (DMF) to CDER, are suit-

able for the ETP program if they include

a proposed technology with potential to

improve product safety, identity, strength,

quality and purity, and that includes one or

more elements subject to quality assess-

ment for which FDA has limited review or

inspection experience.

Top Emerging TechSome examples of emerging technologies

considered by the ETT include continu-

ous manufacturing, additive manufactur-

ing, ultra-long-acting oral formulations,

model-based control strategies, next-

generation sequencing, predictive model-

ing for process monitoring, isolators for

aseptic filling, and novel container and

closure systems for injectables.2

There are several other technology-

based trends that will transform the phar-

maceutical industry, according to Bertalan

Mesko, a recognized author and speaker

who considers himself to be the “Medical

Futurist.” Bertalan’s top-ten list of disrup-

tive technologies includes the following:3

1. Empowered patients, which will require technologies that enable communication, education and ensure effective interaction between pharmaceutical companies and the people using their products.

In many cases, nanotechnology is being

investigated as a means for improving effi-

ciency and reducing cost while providing

novel functionality. In drug discovery, for

instance, nanotechnology is enabling high-

throughput screening via miniaturization

of analytical tools. It is also enabling the

design of lab-on-a-chip diagnostic tests

for point-of-care use and greater resolu-

tion and accuracy in medical imaging.10

In drug delivery applications, nano-

suspensions, nanoemulsions and nano-

micells are used to synthesize various

nanoparticle-based materials for the

formulation of advanced drug products.

Using these technologies can improve

drug performance by increasing bioavail-

ability and stability, prolonging activity,

reducing dosing frequencies and allow-

ing for drug targeting.12

A Note on Emerging Technology in the Contract Services ArenaThe importance of emerging technolo-

gies for contract manufacturers and

research organizations was clearly high-

Examples of emerging technologies include continuous manufacturing, additive manufacturing, ultra-long-acting oral formulations, model-based control strategies, next-generation sequencing, predictive modeling for process monitoring and isolators for aseptic filling.

REFERENCES

1.Sau (Larry) Lee and Kurt Brorson. “Emerging

Technology As A Key Enabler For Modernizing

Pharmaceutical Manufacturing.” PDA Journal of

Pharmaceutical Science and Technology 71.2 (2017): 66-67.

Web.

2. ”Emerging Technology Program.” U.S. Food and Drug

Administration. 29 Sep. 2017. Web.

3. Bertalan Mesko. “10 Disruptive Technologies That Will

Transform Pharma.” The Medical Futurist. Web.

4. FDA Approves The First 3D Printed Drug Product.

Aprecia Pharmaceuticals. 3 Aug. 2015. Web.

5. David Epstein. “The Next Horizon Of Innovation For

Pharma.” Mckinsey. Mar. 2017. Web.

6. Technical Considerations for Additive Manufactured

Devices: Draft Guidance for Industry and Food and Drug

Administration Staff. U.S. Food and Drug Administration.

10 May 2016. Web.

7. Jennifer Markarian. “FDA And The Emerging Technology

Of 3D Printing.” Pharmaceutical Technology 40.8 (2016).

Web.

8. Jennifer Markarian. “Using 3D Printing for Solid-

Dosage Drugs.” Pharmaceutical Technology 40.8 (2016):

34-36. Web.

9. Niklas Sandler, Akm Khairuzzaman. “A New Chapter

In Pharmaceutical Technology: 3D Printing For Solid Oral

Dosage Forms.” AAPS Blog. 9 Nov. 2016. Web.

10. Mike Fisher. “Nanotechnology In The Biotechnology

And Pharmaceutical Industries.” Medical Technology

Business Europe. Oct. 2008. Web.

11. Nanomedicine Market Size Worth $350.8 Billion By

2025 | CAGR: 11.2%. Grand View Research. Apr. 2017. Web.

12. Ram S. Thakur, Ruchi Agrawal. “Application Of

Nanotechnology In Pharmaceutical Formulation Design

And Development.” Current Drug Therapy 10.1 (2015):

20-34. Web.

13. CDMO - 2017 Nice Insight Contract Development and

Manufacturing Survey.

14. CRO - 2017 Nice Insight Preclinical and Clinical

Contract Research Survey.

ABOUT THE AUTHOR

Nigel Walker Managing Director, That’s Nice LLC / Nice Insight

Mr. Walker is the founder and managing director of That’s Nice LLC, a research-driven marketing agency with 20 years dedicated to life sciences. Nigel harnesses the strategic capabilities of Nice Insight, the research arm of That’s Nice, to help companies communicate science-based visions to grow their businesses. Mr. Walker earned a bachelor’s degree in graphic design with honors from London College.

LinkedIn www.linkedin.com/in/walkernigelEmail [email protected]

lighted in the 2017 Nice Insight surveys

of top executives in the pharma industry.

Cost was initially the main driver for

outsourcing. In 2016, it was the desire

to improve quality. In 2017, however, the

top reason for outsourcing by survey

respondents to both CDMOs13 and CROs14

was access to specialized technologies.

The surveys also revealed that contract

service providers that can offer novel and

proprietary technologies in conjunction

with the ability to form long-term, stra-

tegic partnerships, acting as extensions

and providing comprehensive, efficient,

responsive and affordable support, are

most successful at attracting and retain-

ing desirable pharmaceutical industry

customers. P

Cost was initially the main driver for outsourcing. In 2016, it was the desire to improve quality. In 2017, however, the top reason for outsourcing by survey respondents to both CDMOs and CROs was access to specialized technologies.

There is significant potential for nanotechnology to be applied in the pharmaceutical industry, from smart materials for tissue engineering to intelligent tools for drug delivery.

Global Nanomedicine Market Compound Annual Growth Rate

$350.8B by 2025

11.2%

MORE TRIALS IN REMOTE LOCATIONSClinical trials have become increasingly global in nature. In some

cases, there is a need to demonstrate improved efficacy over

existing products, which requires a large number of patients

in different geographic locations. For drugs designed to treat

chronic diseases, extended trial times across many locations

are often required. With the percentage of orphan drugs in the

pharmaceutical pipeline, there is a need to enroll patients from

many more countries, often in remote locations with little medi-

cal support services. Personalized therapeutics such as cell and

gene therapies, which account for a growing number of drug can-

didates in clinical trials today, require full visibility and tracking

from patients to distant manufacturing locations and back again,

within limited time periods.

Greater demand for direct-to-patient (DTP) services, in which

patients receive treatment and have blood samples drawn and

prepared for shipment at their homes, is one outcome of these

trends. DTP clinical trials services are particularly beneficial

for studies involving orphan drugs, which often require the en-

rollment of patients in remote locations, as well as drugs for the

treatment of patients with limited capacities, and children. They

also often result in improved patient retention and compliance

with protocols.

TEMPERATURE-SENSITIVE MEDICINES Compared to commercial drug products, clinical trial materials

(CTM) are produced in small quantities and according to speci-

fied manufacturing protocols. There is typically limited data

available with respect to the stability of the formulated products.

Expiration dates are therefore often very short. Many are biolog-

ics, which are also temperature sensitive and require shipment at

controlled temperatures such as -20C, 2-8C or other ranges. Most

are high-value products with costs per dose in the thousands of

dollars. Given these issues, just-in-time shipment of clinical trial

ack of effective management of the outbound distribution of clinical trial materials can negatively impact study outcomes and ultimately prevent medications from reaching patients in need. With growing numbers of studies across a wider range of locations involving complex protocols and in-home

participation, clinical logistics organizations have become important enablers of effective clinical drug distribution.

INDUSTRY LEADER I NSI GH T

> BY WES WHEELER AND ARIETTE VAN STRIEN, MARKEN

OUTBOUND CLINICAL DRUG DISTRIBUTION

MARKEN BY THE NUMBERS

49,000# Of Investigator Sites Supported

800+# Of Full-Time Employees

220+# Of Countries Serviced

46# Of Global Locations

10# Of GMP Depots

100%Dedicated To Pharma

MANAGING THE COMPLEXITIES OF


There is, however, a need to be more sus-

tainable while meeting shorter and shorter

turnaround times. While these solutions

have facilitated the choice of packaging

materials for distribution of temperature-

sensitive clinical trial materials, they have

made the return of reusable packaging

more complicated. Many of these solu-

tions are based on specific phase-change

materials. As a result, there are thousands

of packages used to ship clinical trial ma-

terials at any given time that must be re-

turned in an efficient manner back to their

origin or the closest packaging condition

hub for reconditioning and reuse.

Reconditioning is a detailed and docu-

mented process. Each container must be

inspected to ensure that it has not been

damaged. Testing should be conducted

to confirm that pinhole leaks or moisture

absorption have not affected the perfor-

mance of the vacuum-insulated panels,

and that the phase change material is not

leaking. The container must be washed

and sanitized. Any damaged materials and

any materials that experience wear during

shipment (such as corrugated cardboard)

must be replaced. Refrigerators, freezers


materials is often necessary, or frequent

replacement of unused materials must be

planned into the protocol in order to keep

overage as low as possible.

Outbound distribution of clinical trial

materials must, of course, also be in com-

pliance with the import/export regulations

of each country that the drugs will be en-

tering and/or departing from on the way to

the patient or investigator site. As trials

become more global and complex, knowl-

edge of differing country requirements is

essential to effective logistics planning.

Compliance with Good Distribution Prac-

tice (GDP) regulations around the world is

required. Exact shipping routes must be

mapped out, in advance, of any clinical

trial material pickup from the pharmaceu-

tical company or contract manufacturer,

including specification of drivers, street

routes, airports, air carriers, flights and

flight numbers, etc. Contingency plans

are critical in case the preferred route

cannot be utilized for any reason.

PACKAGING CHALLENGESDue to the increasing prevalence of clinical

trial materials that require temperature-

controlled shipment, packaging manufac-

turers have invested in the development

of solutions that allow maintenance of a

specific temperature throughout delivery

of the drug product. The need to comply

with GDP requirements has been an ad-

ditional factor in the development of cold

chain solutions. As a result, today there

are many packaging options now available

for most controlled-temperature ship-

ments to match all levels of different tem-

perature ranges needed.

and monitoring systems must be checked

to ensure they are operating correctly. Ef-

fective quality management systems are

essential to ensure procedures and equip-

ment are properly calibrated, maintained

and linked to a monitoring system.

REAL CONSEQUENCES OF IMPROPER LOGISTICS MANAGEMENTEffective management of outbound clini-

cal drug distribution is important to the

success of any clinical trial. If the sup-

ply chain is not operating at peak perfor-

mance and a drug is not delivered and

experiences a temperature excursion,

potentially leading to damage of the prod-

uct, the seamless flow of a trial can be se-

verely impacted.

If a patient does not receive his or her

drug in a timely manner, then he/she may

have to drop out of the trial, which could re-

quire additional patients to be recruited,

if even possible, or impact the overall re-

sults for the study. If an entire batch of

clinical trial material is lost during tran-

sition, the trial could be negatively im-

pacted, which could in turn impact large

numbers of patients.

THIRD-PARTY LOGISTICS PROVIDERS CAN MEET THE CHALLENGEGiven the combination of tremendous

complexity and the potential for signifi-

cant negative consequences of ineffec-

tive outbound clinical drug distribution,

many pharmaceutical companies turn

to third-party logistics service providers

— supply chain logistics providers — to

manage these activities. A company that

focuses on clinical trial logistics is able

to develop the depth and breadth of ex-

pertise and knowledge required to ensure

the smooth passage of drug products

from the manufacturer to the patient.

They are experts in regulations in all of

the countries around the world in which

clinical trials take place, and they develop

the most secure routes and methods for

shipping clinical drug products.

For instance, because Marken is 100%

dedicated to providing clinical logistics

services and has served approximately

900 customers, each with their own spe-

cific requirements, we have amassed a

substantial body of knowledge. We have

a true understanding of the regulations in

each country and are in a better position

to take on the risks associated with estab-

lishing the logistics for clinical trial mate-

rials. As a leader in DTP services, we also

facilitate direct-to-patient trials around

the world. We apply our expertise and

knowledge to each new customer scenario,

establishing optimized and cost-effective

clinical logistics solutions.

CHOOSING THE RIGHT DISTRIBUTION STRATEGYSupply chain logistics providers that can

provide a number of different clinical lo-

gistics options are also better positioned

to provide optimum solutions. A clinical

trial for a drug to treat a rare disease may

not have a large number of patients, but

many of those enrolled may be in remote

areas that require DTP services, whereas a

trial for a drug candidate intended to treat

a more common disorder may have large

numbers of patients located in many dif-

ferent countries. Some protocols indicate

that drugs must be distributed from the

investigator site, or through a central phar-

macy, while others may allow for delivery

from a central depot directly to the patient.

A provider with experience supporting

hundreds of different clinical trials has

the expertise needed to determine which

logistics approach will be most effective

— for instance, delivery from the manufac-

turer first to a depot site and then the in-

vestigator site, or directly to the investiga-

tor site. Factors to be considered include

the number of overall patients, the number

of patients in different countries and in

remote versus central areas, the stability

of the drug itself, the value of the drug and


For more than 35 years, Marken has focused on the evolving nature of

the pharmaceutical industry, developing and implementing innovative solutions that anticipate the changing needs of our clients. Our ability to innovate for the clinical trial industry results from the fact that we only serve pharmaceutical and life science clients, working strategically with our clients and all other external partners to identify unmet needs before they occur. Our systems are designed specifically to reduce the risks associated with clinical materials supply and biological sample shipments, facilitate regulatory compliance, increase supply chain efficiency and productivity, and reduce costs.

In addition to our standard and new hybrid clinical material logistics services, Marken

Secure Specialty Services

offers highly secure, truly personalized specialty clinical trial logistics services. These specialty logistics services include biological sample shipments, including a collection of patient samples at their homes. With our state-of-the-art GMP-compliant depot network, logistic hubs for clinical trial material storage and distribution locations worldwide and extensive experience with DTP services, we successfully manage 50,000 drug and biological shipments every month — at all temperature ranges — in more than 220 countries.

Marken is the leading provider of patient-centric supply chain solutions for clinical trial materials and sensitive drug shipments worldwide, now with an enhanced offering that delivers maximum efficiency. As the clinical subsidiary of UPS, Marken’s global scale of clinical supply chain solutions is more equipped than ever to meet the increasingly complex needs of its clients, with no geographic boundaries.

We currently offer DTP services associated with over 100 active clinical trials that involve more than 1,600 investigator sites.

import license requirements.

If a protocol only indicates that a drug

should go to the investigator site, the de-

cision must be made whether to ship to a

depot first. This decision will depend on

any potential issues that may arise along

the shipment route, such as any potential

inspections for Customs clearance. If im-

port requirements are complex, the drug

product is stable and there is sufficient

clinical trial material available, shipping

to a depot would be recommended. On the

other hand, if only small quantities of the

drug product are available, and if it is clear

that the drug can be delivered in a timely

fashion and cost calculations are accept-

able, then shipping directly to the investi-

gator site might be preferable.

For direct-to-patient trials, the same

questions must be addressed — deliver to

the investigator site for dispensation or to

a depot, from which the drug is delivered to

the patient. In either case, the investigator

site or central pharmacy must be responsi-

ble for dispensing the drug to the patient’s

home. Marken has experience with cen-

tral pharmacies, which enables us to store

clinical trial materials in a central GMP-

compliant depot and dispatch the drugs to

patients in their homes.

Clinical Supply Chain Logistics

Marken continues to expand this comprehensive network with additional strategically located sites, adding new locations as needed to maintain or increase focus in areas of clinical trial growth.


ABOUT THE AUTHORS

Wes Wheeler Chief Executive Officer, Marken

Wes Wheeler joined Marken in 2011 to transform the company, which has grown to more than 40 locations in 19 countries throughout the world. Wes joined the pharmaceutical industry in 1989 with Glaxo (now GlaxoSmithKline) and has served as CEO/President at four different companies. Prior to 1989, he worked for 12 years as an engineer for Exxon (now ExxonMobil). Wes holds a bachelor of science degree in mechanical engineering from Worcester Polytechnic Institute and a masters in business administration with an emphasis in finance.

LinkedIn www.linkedin.com/in/wes-wheeler-504b815 Email [email protected]

Ariette van Strien Chief Commercial Officer, Marken

Ariette van Strien is Marken’s voice of the customer, having spent 25 years in the clinical research industry, with the last six years developing new services for Marken, spanning sales, marketing, business development, and global operational and project management roles. Having worked on the central lab and clinical side, Ariette brings a unique perspective from this portion of the supply chain. Ariette has a diploma as a National Public Relation Consultant, a Superior French Language degree from the International College of Cannes, and a baccalaureate of modern languages and biological sciences.

LinkedIn www.linkedin.com/in/ariette-van-strien-0706144 Email [email protected]

GMP DEPOT

DRUGINNOVATOR

SPECIALTY LAB

INVESTIGATORSITE

CENTRALLAB

PATIENT

REGULATORY

CRO

TRADECOMPLIANCE

TRACK& TRACE

MEDICAL DEVICE MANUFACTURER

SECURITY

CMO

NETWORK

THE LIFEBLOOD OF YOUR CLINICAL SUPPLY CHAINMARKEN’S INTEGRATED OFFERING MEANS RELIABILITY AND FLEXIBILITY ACROSS YOUR SUPPLY CHAIN

Marken’s market-leading breadth of services is stronger than ever, delivering the core specialty clinical trials solutions our clients have come to rely on, now with standard and hybrid offerings that leverage a global transportation network. As the clinical subsidiary of UPS, Marken continues to be fully committed to serving the clinical trials community with exceptional quality and optimized efficiency.

Talk To Us About Your Logistics [email protected] | www.marken.com

PAQ417_Marken.indd 1 10/13/17 5:27 PM

Most personalized treatments, such

as autologous cell and gene therapies,

pose many more challenges. These clini-

cal trial materials may be bio-hazardous,

and require special handling at all tem-

perature-controlled ranges, typically at

cryogenic storage conditions. An effec-

tive chain of identity must also be estab-

lished. Highly sophisticated scheduling

details ensure that the advanced therapy

medicinal product (ATMP) is safely de-

livered back to the correct patient at the

predefined time. The supply chain must

be fully mapped from each investigator

site and, if applicable, from each apher-

esis center to the manufacturing site. The

patient-specific tracking of their unique

samples, as well as their own ATMP re-

turned back to the patient, is key to the

success of these treatments. Recognizing

the specificity of these treatments and

the close collaboration needed with all

involved partners, along with the proac-

tive planning needed, creates the ground-

work for a successful outcome. Choosing

the best distribution model is dependent

on the regulations, protocol and patient

schedule, which should be discussed and

outlined with the client prior to the start

of the trial.

END-TO-END VISIBILITY IS ALSO ESSENTIALOne other clear current mandate of the

industry is to provide a complete end-to-

end visibility for shipments. Marken of-

fers cloud-based shipment tracking from

booking to delivery through the use of

state-of-the-art GPS technology.

The Sentry and Sentinel GPS trackers,

available exclusively to Marken, allow

real-time GPS tracking of a package’s

location (and each component within a

shipment), monitoring of any temperature

variations, vibration, light and shock, and

provides for geofencing and complete

end-to-end visibility.

To be most effective, however, it is

essential that suppliers like Marken are

an integral part of clinical trial set-up to

ensure that their experience, expertise

and technical capabilities are appropri-

ately utilized and leveraged so that the

supply chain solution for each protocol

is optimized.

FLEXIBLE, GLOBAL NETWORKS LEAD TO SUCCESSMarken has an unparalleled network con-

sisting of 46 global customer service and

operational locations, including 10 GMP

storage depots, allowing drug product

manufactured in the US, Europe, Asia or

elsewhere to be delivered as close as pos-

sible to preselected clinical trial investi-

gator sites and patients. Local qualified

service providers with intimate knowl-

edge of evolving local regulations work

in close cooperation with the Marken

network to provide services in areas with

fewer patients. We provide 24-hour con-

trol of our network.

Over the past several years, Marken

has focused on building a team of experts

with not only logistics expertise, but also

with experience working for pharmaceuti-

cal companies, contract research labora-

tories, contract manufacturers and pack-

aging firms. As a result, we have a strong

grounding in the fundamentals of clinical

trial protocols to develop the most appro-

priate supply chain solutions.

We continue to expand this comprehen-

sive network with additional strategically

located sites, adding new locations as

needed to maintain or increase focus in

areas of clinical trial growth. P

Marken is also a leading provider of direct-to-patient (DTP) services, managing a large portfolio of active DTP trials, including global trials with more than 15,000 patients.


> GENE THERAPY FACILITY DESIGN


SEGREGATION IN THE DESIGN OF GENETHERAPY MANUFACTURING FACILITIES

SIGNIFICANT MARKET POTENTIAL

While the current market for gene ther-

apies is small, with just seven drugs

approved to date (four in China, two in

Europe and one in the US), there are at

least 12 additional candidates that have

reached late-stage clinical trials, leading

to expectations for significant growth in

the coming years.1 Many large bio/phar-

maceutical companies and a number

of emerging and medium-sized biotech

firms are developing gene therapies as

treatments for cancer; hemophilia; neu-

rological, ocular and cardiovascular dis-

eases; and many other disorders that

often have no existing cure or require

repeated treatment with existing drugs.

Roots Analysis identified 483 gene ther-

apy molecules in the marketed and clini-

cal pipelines in 2015.1

From January 2013 to April 2014, US

companies raised $600 million to support

their gene therapy development programs.1

Novartis recently received FDA approval

for chimeric antigen receptor T (CAR-T)

cell therapy Kymriah™, for the treatment

of patients with B-cell precursor acute lym-

phoblastic leukemia (ALL). Kymriah, which

uses a patient’s own T cells to fight cancer,

is the first FDA-approved therapy based on

gene transfer. FDA is expected to approve

the second gene therapy for the US mar-

ket in 2018, with the most likely candidate

being Spark Therapeutics’ Luxterna, a

treatment for Leber Congenital Amauro-

sis, a genetic eye disorder that leaves suf-

ferers legally blind by the age of 21, which

was granted priority review by FDA in late

August 2017.2 A decision from the agency

is expected in mid-January. Overall, Roots

Analysis predicts the global gene therapy

market to grow by 48.9% annually to reach

a value of $11 billion by 2025.1

MINIMIZING CROSS-CONTAMINATION RISK

Manufacturing processes that involve the

replication of a virus present several chal-

lenges with respect to facility design and

equipment selection. Virus particles are on

the nanometer scale and can pass through

standard 0.2 micron “sterile barrier” fil-

ters used in typical process systems. As a

result, there is a higher risk of them being

spread throughout areas in which they are

used, thus presenting a potential risk for

environmental contamination. This carries

impacts for process operations and oper-

ator health and safety. Virus particles

from one process could potentially cross-

contaminate other processes completed

in a multiproduct facility. More controls

are therefore required to segregate and

contain these process streams from other

parts of the manufacturing plant.

ENVIRONMENTAL SEGREGATION

The biggest differentiating concern for

production facilities using viruses is the

risk of cross-contamination. For any single

product facility, it is necessary to prevent

contamination of process steps by adven-

titious agents. For multiproduction facili-

ties manufacturing two or more different

gene therapy vectors, it is essential to pre-

vent helper virus particles or the product

vector from one process contaminating

the other. In both cases, the processes

must be environmentally segregated from

the remainder of the facility.

THE IMPORTANCE OF PROCESS MAPPING

To create an appropriate design for a

gene therapy manufacturing facility that

provides the necessary level of environ-

mental segregation, the design engineers

must be familiar with all the specific pro-

cess operations that will be performed.

Constructing a process map for all of the

intended processes in the facility from an

operational perspective can be a key tool

for communicating process requirements.

Specific requirements for each process —

equipment, material flows, personnel move-

ments, etc. — must be considered. The level

of desired operational flexibility within the

facility should also be factored. A process

equipment closure analysis — whether

the process steps used with the selected

equipment are performed open to the envi-

ronment, briefly exposed, closed or func-

tionally closed — should be performed and

documented as part of the facility basis of

design. The choice of stainless steel, dis-

posable or hybrid systems may factor into

these considerations. Understanding of

requirements and regulatory guidance will

determine which processes can be per-

formed side by side in the same room, and

which must be conducted in segregated

areas of the facility. Space requirements

will impact the environmental air handling

schemes such as room classification and

HVAC planning.

For most closed pharmaceutical pro-

cesses (when the process is completely

contained and separated from the produc-

tion environment), introduction or removal

of gases and fluids are through system

boundary filtration. While these filters

are typically sized to capture most envi-

ronmental contaminants such as bacteria

and particulates, viral particles (typically

20-100 nm) can pass through. Their dimin-

utive size makes viral particles especially

difficult to contain when producing and

processing in large quantities. Therefore,

the steps within a manufacturing process

that involve the use of viruses are generally

segregated completely from other process

areas within the same facility. Similarly, it

is important to map out the movement of

all materials containing, or that may have

come into contact with, virus particles.

GMP flow diagrams depicting the move-

ment of materials, people, equipment,

waste and product are critical in challeng-

ing the design and ensuring that contami-

nation and cross-contamination risks are

understood and suitably mitigated. HVAC

diagrams depicting air handler zoning,

room classifications and room pressuriza-

tion must also be reviewed to ensure that

air systems do not transport contamina-

tion from one area to another.

PREPARATION, PRODUCTION

AND PURIFICATION

Manufacturing of gene therapies involves

many different process steps and opera-

tions, including weighing and dispensing

of raw materials (including powders and

liquids), solution formulation, growing and

infecting host cells, and numerous down-

stream purification steps.

Weigh and dispense activities are typi-

cally handled in a separate room. Media

powders are by design growth promoting,

and present a higher risk of containing

contaminating viruses. Dust containment

exhaust systems or closed powder addi-

tion systems are used to enable contain-

ment of raw materials during open han-

dling. If raw materials are weighed and

dispensed into functionally closed powder

addition systems, solution formulation can

A number of gene therapies are in late-stage clinical trials and expected to reach the market in the next several years. Unlike traditional biologic drugs, gene therapy production can involve the manipulation of replication of viruses. Segregation of manufacturing operations involving viruses is a crucial consideration when designing processes and overall facilities.

> PETER WALTERS, CRB USA

THE BIGGEST DIFFERENTIATING CONCERN FOR PRODUCTION FACILITIES USING VIRUSES IS THE RISK OF CROSS-CONTAMINATION.


be performed in the same space as the pro-

cess that is being prepared for. However,

it may nonetheless be desirable from an

operations standpoint to group all solution

preparation into a central segregated solu-

tion preparation suite.

Cell-culture initiation and expansion

operations prior to infection can be con-

ducted just as cell-culture processes for

the production of monoclonal antibod-

ies (mAbs) and therapeutic proteins. The

industry has accepted that the function-

ally closed upstream production trains for

therapeutic proteins, but not viral opera-

tions, can be deployed using an open ball-

room approach. The ballroom approach

features a large open operational space

where closed processing equipment can be

co-located in the same space. Examples

include mAb seed trains and production

bioreactors operating side by side. To mit-

igate the risks of cross-contamination, all

of these activities should be segregated

from steps that involve the use of viruses.

Processes involving host cell infection,

viral production, purification and product

formulation should be spatially segregated

in a separate room in order to contain vec-

tor particles within a specified zone in the

facility. For HVAC, these spaces should uti-

lize dedicated air handling units or single

pass air flow to minimize contamination

risks. Here, too, as long as each process is

performed in a functionally closed equip-

ment train, the process steps may be con-

ducted in the same room. For multiprod-

uct facilities, processing of multiple gene

vectors should be performed either on a

temporally segregated campaign basis

(with sanitization between) or in parallel

but in completely segregated viral pro-

duction spaces for each product cam-

paign produced.

Vector drug product filling is a low-

volume, low-speed operation, and is typi-

cally performed using isolator filling sys-

tems. As with other filling operations, these

have higher room classification require-

ments and their own dedicated spaces.

Unlike mAbs or therapeutic proteins, how-

ever, these filling systems must be decon-

taminated to inactivate any residual vector

presence within the filling isolator prior to

equipment opening and changeover.

STAINLESS, DISPOSABLE AND

HYBRID EQUIPMENT SOLUTIONS

Selection of the equipment used for

gene therapy manufacturing can have a

significant impact on the level of effort

and cost required to segregate produc-

tion steps from the surrounding environ-

ment. The pharmaceutical equipment

industry has well-developed solutions for

the production of mAbs and other thera-

peutic proteins, and similar solutions are

used for these steps within the overall

gene therapy manufacturing process.

There are stainless steel or disposable

equipment solutions available and well-

developed methods for selecting the

best options based on specific process

and throughput requirements.

For the viral vector processing steps,

because it is necessary to demonstrate

complete removal of all virus particles

between campaigns, single-use systems

are attractive. These come pre-sterilized

and eliminate the need for cleaning and

cleaning validation, thus reducing the

risk of cross-contamination, while also

reducing downtime and cleaning costs.

The use of disposable technologies may

significantly simplify the overall produc-

tion facility due to reductions (or elimina-

tions) of utility systems and simplification

of automation. Construction, validation

and start-up of facilities utilizing dispos-

able equipment are typically much faster

and less expensive than their stainless

steel counterparts. Complete dispos-

able pre-sterilized systems may also be

easier to close for processing, which in

turn can enable for lower room classifica-

tions that require less extensive mechani-

cal equipment (e.g., airlocks, air handling

systems) and can lead to smaller produc-

tion spaces and lower facility costs. Even

so, the performance of a cost analysis is

recommended to confirm that disposable

technologies are advantageous. The cost

of goods with these systems can be highly

impacted by run rates and other factors,

and in some cases, hybrid solutions using

both stainless steel and disposable sys-

tems may be more appropriate.

BESPOKE DESIGN IS THE BEST SOLUTION

Given the challenges associated with

gene therapy vector manufacturing, at

CRB we take a client-focused approach

to facility design, drilling down through

each process to consider all relevant fac-

tors. One of our goals is to reduce the

need for equipment movement and the

number of necessary rooms, and thus the

production-area footprint, while still pro-

viding appropriate safety and environ-

mental controls, logical flows of materi-

als and personnel, and better equipment

usability for operators. This bespoke

design process allows for greater facility

flexibility while ensuring efficient pro-

duction processes and operator safety. P

REFERENCES

1. Gene Therapy Market, 2015 – 2025. Roots Analysis. Feb. 2015. Web.2. Lovell, Ethan “Opinion: How investors should play gene-therapy Stocks,” Marketwatch.com. 6 Sept. 2017. Web.

ABOUT THE AUTHOR Peter Walters Lead Process Engineer, CRB USA

Peter Walters is a lead process engineer at CRB, specializing in biological process and facility design. He oversees conceptual and detailed design, multi-discipline coordination, and generation of design deliverables, including design narratives, P&IDs, material and energy balances, facility arrangement drawings, process simulations, cost analysis and specialized reports. Peter graduated from the University of California, Davis, with a degree in chemical/biochemical engineering. He is a Southern California native and enjoys playing soccer and spending time with his family in San Diego.

LinkedIn www.linkedin.com/in/peter-walters-96093a11/ Email [email protected]

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oday there are four commercial ADCs (Adcetris®,

Kadcyla®, Besponsa® and Mylotarg®) on the market1 —

though there is enormous potential up the pipeline.

At the end of 2016, some 60 ADCs were in early-stage

trials, with one undergoing regulatory review and two

more in phase III trials.2

Despite many originators investing in manufacturing, con-

tract development and manufacturing organizations (CDMOs)

play a huge role in this industry. Some 40 CDMOs currently

provide ADC-specific services, about 20 make cytotoxics and

offer conjugation and 15 have relevant fill-finish capabilities,

though few offer a true integrated capability.2

Research & Markets and Roots Analysis, who both published

global market reports on ADCs in 2015, estimate that over 70% of

ADC manufacturing is outsourced. The former projects the global

market for contract manufacturing of ADCs at $1 billion by 2018,

which is 36% of the forecast total market value of $2.8 billion.2

CDMOs INVESTINGCDMOs have also been investing in recent years to ex-

pand their facilities, buying companies with related

expertise. Many of these originally expanded into ADCs from a

core expertise in cytotoxics or HPAPIs in general; others come

from the biologics or fill-finish sides of the business.

Lonza is a pioneer in ADCs, supplying the conjugates for both

Adcetris and Kadcyla. Conjugation and related activities are based

at Visp, Switzerland, where the company carries out both small

molecule process development and scale-up and mammalian cell

biomanufacturing for multiple highly potent biopharmaceuticals.

Lonza now offers an ‘Easy Access ADC Program,’ including prepa-

ration of sample panels using linker, drug and mAb combinations.

Later-stage capabilities are built on multipurpose cGMP plants

VIRTUAL PANEL

THE CONTRACT MANUFACTURING MARKET FOR ANTIBODY-DRUG CONJUGATES HAS HUGE POTENTIAL, BUT AN EXTRAORDINARY RANGE OF CAPABILITIES IS ESSENTIAL TO BE IN THE GAME. WE SPOKE TO SOME OF THE PLAYERS TO FIND OUT ALL ABOUT ADCs.

T Thomas Rohrer Associate Director of

Bioconjugate Commercial

Development, Lonza

> ABOUT THE PANELISTS

> BY GUY TIENE, NICE INSIGHT

ADCs: THE FUTURE OF BIOLOGIC DRUGS

Mark Wright, Ph.D. Site Lead, Piramal Healthcare

Jean Bléhaut President of the Synthesis

Business Unit, Novasep


dedicated to ADC drug substance at scales

from 10 to 600 liters.

“ADCs are very complicated from the

standpoint of the intermediates required

to manufacture them,” says Tom Rohrer,

Associate Director of Bioconjugate Com-

mercial Development. Lonza, he adds,

can make the antibody, the linker and the

cytotoxin, both semi-synthetic or fully syn-

thetic cytotoxins and can work with pretty

much any linker. There is also investment

in recruiting talent with experience in drug

product development and manufacture,

including bioconjugates. Because ADCs

require a smaller amount of antibody due

to their higher potency, Lonza has also

expanded capacity at its Slough, UK site

to make small batches. “This helps us

tremendously because many companies

coming to us may not have access to suf-

ficient quantities of antibodies to execute

their programs,” Rohrer says.

Now part of Piramal Healthcare, the

site at Grangemouth, UK has been active

in ADCs since 2004. Piramal states that

it has manufactured over 600 batches of

ADCs, more than half to GMP and over

100 of them commercial. This work cov-

ers over 460 batches made of phase III/

commercial ADCs.3 In September 2015,

Piramal set a target of becoming the world

leader in ADC contract manufacture by

2021. Earlier that year, it acquired Cold-

stream Laboratories, a specialized ADC

fill-finish site in Lexington, Kentucky,

which it described as “the final piece

in the jigsaw puzzle.” It simultaneously

launched a new ‘Proof of Concept’ service

designed to speed the development of the

most promising targets.4

Since then, says Mark Wright, Site Lead

at Grangemouth, “Piramal has acquired

Ash Stevens, a specialist in HPAPIs, has

expanded the fill-finish capabilities at the

Riverview, Michigan site and is now look-

ing at upgrading the high-containment

capabilities for ADC payload production.

A plan should be presented to the board

within months for an additional conjuga-

tion suite at Grangemouth to add larger-

scale batch capacity.”

FLEXIBLE PRODUCTIONNovasep has been a contract service pro-

vider in the ADC arena for more than ten

years. The company announced in June

2015 that it would build a fully integrated

conjugation facility at its Le Mans site, with

ALLIANCES FORMEDThere have also been collaborations in the

field by CDMOs seeking to offer a com-

plete package. Even before being acquired

by Piramal, Coldstream was working with

Goodwin Biotechnology. Piramal also has

a long-standing partnership with Fujifilm

Diosynth Biotechnologies to supply mAbs.

“This is more than just an alliance —

our scientists and Fujifilm’s collaborate

closely, leading to both time and efficiency

savings for clients,” says Wright. Moreover,

where before clients were more likely to

take an existing mAb and then evaluate it

for conjugation, now they are increasingly

making the mAb with the specific intention

of conjugating it.

As of March 2016, Novasep formed a

partnership with its French compatriot

GTP Technology for preclinical and early

clinical mAb production. “We can also

leverage a couple of other partners to de-

velop a cell line and are now in several proj-

ects where we develop mAbs for customers

from scratch, GTP can take us to the non-

GMP stage and we take over again with

GMP manufacturing,” says Bléhaut.

DRIVERS TO OUTSOURCEADC developers outsource for various rea-

sons. Some seek flexibility or to avoid capi-

tal investment in highly specialized facili-

ties that risk low utilization, while others

are put off by the complex operations re-

quired. Whether customers, in general,

prefer the proverbial one-stop shop that

can offer all or nearly all operations under

a single roof is an open question.

“Biotechs like it that we have every-

thing in-house and to have somebody who

can do it all,” says Miller. “We can manage

the whole process and they don’t need to

worry about getting different materials

moved between different vendors, and it’s

all managed by one person. Big Pharma

firms know the game already and are more

willing to outsource multiple steps to dif-

ferent partners.”

Haering agrees, noting that small bio-

tech companies and start-ups “are defi-

nitely outsourcing 100% of their GMP

production. Large biotechs, on the other

hand, have certain competencies in-house

and outsource only one or two elements of

the ADC manufacturing,” he says.

All concur that the 70% figure for total

outsourcing in the ADC market sounds

reasonable in terms of total volume — and

“Carbogen Amcis can carry out most

ADC-related services in-house, barring

some parts of the analytical side, such

as mass spectrometry (MS) for the whole

conjugate,” adds Miller. “One of the

things unique to our service, perhaps,

is having knowledge from the Design of

Experiments (DoE) approach of how to

bring a product from bench top to com-

mercial,” he says.

Cerbios-Pharma, similarly, expanded

into ADCs based on over 20 years’ exper-

tise in handling HPAPIs to SafeBridge Cat-

egory 4 at the Lugano, Switzerland site,

which has now expanded from cytotoxics

into linkers and conjugation. “Toxin pro-

duction and conjugation both need the

highest containment level,” says CEO Ga-

briel Haering. “The two cGMP production

lines we have are perfect for manufactur-

ing since we can cover batches from a few

grams up to 2 kg.”

Cerbios has invested at the R&D level

with additional HPAPI laboratories. “For

ADCs, only investments in analytical

equipment were required to complete the

biological QC lab; toxin, linker and toxi-

cology and clinical batch capacities are

already adequate,” Haering says. An addi-

tional suite has been designed and will be

ready for commercial production in the

next year.

flexible GMP production suites equipped

with 10 to 400-liter vessels, supported by

process R&D, QC and production scale-

up labs. Jean Bléhaut, President of the

Novasep Synthesis business unit, has

confirmed that this 2,000 m2, €11 million

purpose-built facility is now operational.

The investment complements existing ca-

pabilities in commercial-scale payloads,

linkers, and antibodies. A €4 million plant

extension for payload manufacturing was

commissioned in 2014. “We are now ready

to offer a full service for ADCs, but we are

always looking to extend our scope of ser-

vices either internally or through appro-

priate partnerships,” Bléhaut says.

in 2013, Carbogen Amcis announced

two key investments: the $4 million, 100

m2 cleanroom clinical supply facility

dedicated to drug conjugates at the main

Bubendorf site, and a $950,000 upgrade

of the sterile manufacturing area at its

fill-finish site in Riom, France. The firm

moved into conjugation from high po-

tency, explains Dr. Scott Miller, Senior

Scientific Adviser. “Because we made

linkers and toxins, customers asked if we

could also do conjugation and that led to

expanding in this area.”

Key features at Bubendorf include

aseptic and safe handling of highly potent

material at occupational exposure lim-

its (OELs) of <1 µg/m3 over an eight-hour

time-weighted average (8h-TWA). There

are separate areas for reagent and buffer

preparation, equipment sterilization, and

for cGMP conjugation, purification and

packaging, separated by a system of pres-

sure cascades and air locks for material

and personnel. At Riom, Carbogen Amcis

installed a vaporized hydrogen peroxide

disinfection system and two aseptic fill-

ing isolators operating under nitrogen

atmosphere and at a regulated tempera-

ture, expanding the Grade A manufactur-

ing capability at OELs of <1 µg/m3 8h-TWA

and allowing a maximum batch size of up

to 5,000 units in 2 mL vials.

“Having Riom means we can do the

linker and the chemistry, take the anti-

body, do the conjugation and also do the

fill for clinical trials,” Miller says. “Tra-

ditionally, you did the chemistry and the

conjugation, then threw it over the wall

to a formulator. We can integrate a lot of

that internally and it should shorten the

pathways, which is critical when supply-

ing clinical trials.”

this will probably increase. “ADCs occupy

a lot of personnel time, they are very com-

plicated from an analytic standpoint and

tend to tie up more personnel than a typi-

cal biologic or small molecule. So if com-

panies are launching multiple programs, I

would anticipate that, due to internal ana-

lytical needs, they will tend to put a lot of

the programs out into the CMO network,”

Rohrer says.

Wright notes that some drug compa-

nies have preclinical and/or phase I GMP

capacity in-house, but relatively few have

the capacity for phase II onwards. “There

has been an increase in the number of

ADCs but also in the number of CMOs try-

ing to get involved. There is no bandwidth

problem in terms of conjugation, but there

might be a shortage of companies with real

experience in it,” he explains.

The ADC supply chain is very complex,

involving the antibody, linker and

payload, related conjugation activities,

testing and characterization, formulation

Thomas Rohrer, Associate Director of Bioconjugate Commercial Development, Lonza

“ADCs OCCUPY A LOT OF

PERSONNEL TIME, THEY

ARE VERY COMPLICATED

FROM AN ANALYTIC

STANDPOINT AND TEND TO

TIE UP MORE PERSONNEL

THAN A TYPICAL BIOLOGIC

OR SMALL MOLECULE.”


> ABOUT THE PANELISTS

“IN A HIGH-POTENCY

COMPOUND, YOU ARE

PROTECTING THE WORKER

FROM THE PRODUCT; IN A

CONJUGATION SUITE, YOU

ARE WORKING ASEPTICALLY

IN AQUEOUS SYSTEMS AND

PROTECTING THE PRODUCT

FROM THE WORKER, THOUGH

ALSO VICE VERSA IN

THE CASE OF A TOXIN.”

Scott Miller, Ph.D., Senior Scientific Adviser, Carbogen Amcis

“SOME OF THE PAYLOADS

DO NOT CRYSTALLIZE

AND REMAIN AS OILS OR

FOAMS. THE ONLY WAY

TO PURIFY THEM IS BY

CHROMATOGRAPHY AND

IT IS cGMP FOR THE

SUPPLY OF CLINICAL AND

COMMERCIAL MATERIAL.

THIS IS A UNIQUE

CAPABILITY WE HAVE.”

Gabriel Haering, Ph.D., CEO, Cerbios-Pharma

Gabriel Haering, Ph.D. CEO, Cerbios-Pharma

Scott Miller, Ph.D. Senior Scientific Adviser,

Carbogen Amcis


Guy Tiene, MA Strategic Content Director, Nice Insight

Having worked at That’s Nice from 2000 to 2006 as Business Director for many life science accounts, Guy’s new role involves the deployment of strategic content across marketing communications and thought leadership. Guy holds a master’s degree from Columbia University in New York City.

LinkedIn www.linkedin.com/in/guytiene Email [email protected]

and finishing, stability studies and the

required regulatory package. This must

all be brought together at the right time.

Moreover, every ADC product is different

and must be managed accordingly.5

For Haering, managing the supply chain

is “definitely the key issue of ADC manufac-

turing,” he comments. “Customers using

two or more PROVEO alliance partners

will benefit from the site-to-site shipment

procedures already in place and from an

integrated project management system

headed by a ‘super coordinator,’” he adds.

COMPLEX NEEDSConjugation work on ADCs or any other

conjugate is different from a CDMO view-

point, Miller says. “In a high-potency com-

pound, you are protecting the worker from

the product; in a conjugation suite, you

are working aseptically in aqueous sys-

tems and protecting the product from the

worker, though also vice versa in the case

of a toxin.”

Rohrer adds that special attention must

be paid to personnel flows and ensuring

the facility can be properly decontami-

nated. Seal design for the tanks and the

rate of air changeover are key. “An ADC

suite has to operate as an aseptic envi-

ronment, which is one of the typical dif-

ferences from a small molecule suite that

isolates personnel from the product being

manufactured.”

ADCs also call on complicated, some-

times unconventional, analytics at all

stages of the process. CDMOs have in-

vested accordingly. Lonza, for instance,

has formed a dedicated ADC QC analyt-

ics team and has pulled personnel from

traditional biologics and small molecule

QC to support it. “You need much more

equipment, technology and people for the

analysis of ADCs than you would for clas-

sical chemistry,” Bléhaut says. “The ana-

lytics represent a significant part of our

investment because you also need to have

the right tools for the development phases

and for routine cGMP commercial produc-

tion, so we have invested in, for example,

high-resolution MS.”

Cerbios, Haering says, draws on over

ten years of experience in the analytical

methods used in characterizing therapeu-

tic proteins, applying them also to ADCs.

“Moreover, the use of potent method-

ologies such as MS in our R&D allows a

straightforward transfer to QC for method

validation of ADC-related methods like

drug-antibody ratio (DAR).”

“Purification of the payload with high-

pressure chromatography is definitely

important and essential,” Haering adds.

“Some of the payloads do not crystallize

and remain as oils or foams. The only way

to purify them is by chromatography and

it is cGMP for the supply of clinical and

commercial material. This is a unique ca-

pability we have.”

Like many others active in HPAPIs, Car-

bogen Amcis already had a very high ana-

lytical capability, so the level of support

needed for ADCs was already in place.

“Most methods we use are HPLC-based

and it all fits in well with existing quality

systems,” Miller says.

ONCOLOGY — AND MORE?ADCs are commonly oncology therapies.

The panel agrees that this indication

will remain a key driver but has heard of

others on the horizon, notably in hematol-

ogy and antivirals, though these mostly

relate to biomolecules conjugated with

small molecules.

Novasep, according to Bléhaut, has

more in mind. “We think in terms of im-

munoconjugates, and even more gener-

ally conjugates, because we can couple a

highly potent payload onto a polymer or a

peptide as well. We definitely aim at cov-

ering these various possibilities, which

offer applications that go beyond oncol-

ogy,” he says.

Wright says that he has seen an increase

in interest in anti-infectives using conju-

gation technology. “There could be poten-

tial for antimicrobial-resistant antibiotics

and antivirals, whose development was

hindered by toxicity issues, if they are

made more targeted, possibly with the

addition of selective turning-off of parts

of the immune system.”

Miller adds: “I see some literature

about other areas of research, but by the

time anything gets to us it is in the clini-

cal and early-phase area. For us, it has all

been oncology and it will stay that way in

the near term. I suspect the payback is

faster and the clinical trials easier to set

up in oncology.”

Rohrer adds that the application of tar-

geted therapy will continue to broaden

and is already being seen in combination

vaccines and in antibiotics. Targeted anti-

bodies and nanoparticles are also moving

forward. “All of these require conjugation

of a biological or targeting molecule with

a small molecule or nanoparticle, so the

market will broaden, there’s no question

about that. Conjugation chemistry is the

key, and the biology is tremendously com-

plex. I think that conjugation technology

will be deployed to slow the rate of clear-

ance of small molecules,” he notes.

NEW GENERATIONOf course, like with all new drug develop-

ment, there are challenges. “We all prob-

ably underestimated the biology involved

in ADCs. We looked at it too simplistically

and assumed that you can attach just

about any small molecule cytotoxin as

long as the linker is stable and expect a

biological effect,” says Rohrer. “That

doesn’t work,” he adds.

For Bléhaut, development is now focused

on a new generation of ADCs, where the

objectives are to control DAR and stability.

“This is why we see a lot of new technolo-

gies arising, and also may be why a little

more time is needed for ADCs to come

onto the market,” he suggests.

Wright observes that many of the first

generation of ADCs did not fare so well in

later phases. Quite often, this was because

although their standard toxicity profiles

were reasonably good, specific issues re-

lated to the payloads were discovered only

once they were exposed to a larger number

of patients.

“The other driver is diagnostics and

selection of patients,” Miller adds. “The

ability to find the subset and genomic

profile of the people who take it is cru-

cial — different profiles exist for different

nationalities and regions. Customization

of the treatment is going to be critical

going forward.”

All agree that success for future com-

pounds will depend more on technologies

than their intrinsic properties. Although

cysteines and lysines still account for

about 75% of the linkers used, the loca-

tions of these residues on the antibody

vary, leading to heterogeneous conjuga-

tion. Technologies that offer more ho-

mogeneous conjugation can improve the

therapeutic properties of the ADCs. Some

coming forward are selective N-terminal

conjugation and site-specific function-

alization of glutamines and protein en-

gineering, facilitating new conjugation

chemistries like enzymatic ligation and

click reactions.6

“A number of platforms are developing

in that area and it is hard to say which will

become successful, but the nice thing is

that there is a wide array of technologies

for site-specific conjugation,” says No-

vasep’s Bléhaut. “We are currently doing

some internal R&D work in this field, look-

ing at process robustness studies.”

Rohrer confirms that Lonza is look-

ing at various linker technologies. Site-

specific conjugation, he adds, may have

actually held back some development pro-

grams on second-generation candidates,

because some companies watched to see

technologies develop before committing

themselves. “We have seen a lot of site-

directed conjugation technology coming

through, with stable coupling between the

targeting agent and the small molecule,”

he says. “This will be what pushes ADCs

back into the limelight, and now we are

seeing a lot of activity.”

Miller agrees that both technology and

regulation are driving the market in this

direction. “I am optimistic for conjugates

in general, and there may be a break-

through with a less expensive scaffold — a

polymer, a monomer, a protein, a peptide

or an antibody fragment,” he says. P

Jean Bléhaut, President of the Synthesis Business Unit, Novasep

“WE ARE NOW READY TO

OFFER A FULL SERVICE FOR

ADCs, BUT WE ARE ALWAYS

LOOKING TO EXTEND OUR

SCOPE OF SERVICES EITHER

INTERNALLY OR THROUGH

APPROPRIATE PARTNERSHIPS.”

Mark Wright, Ph.D., Site Lead, Piramal Healthcare

“PIRAMAL HAS ACQUIRED ASH

STEVENS, A SPECIALIST IN

HPAPIs, HAS EXPANDED THE

FILL-FINISH CAPABILITIES

AT THE RIVERVIEW,

MICHIGAN SITE AND IS NOW

LOOKING AT UPGRADING

THE HIGH-CONTAINMENT

CAPABILITIES FOR ADC

PAYLOAD PRODUCTION.”

REFERENCES

1. Dan Stanton. “New dosing regimen brings Mylotarg reapproval for Pfizer.” 5 Sept. 2017. Web2. ADC Contract Manufacturing Market (3rd edition), 2015-2025. Rep. Roots Analysis. 10 Dec. 2015. Web.3. “Global Network.” Piramal Pharma Solutions. Piramal Enterprises Ltd. Web. 4. “Piramal Targets Becoming the Global Market Leader In Development & Manufacturing of Antibody Drug Conjugates (ADCs).” Outsourced Pharma. Piramal Enterprises Ltd. 29 Sept. 2015. Web.5. Cynthia Wooge. “Using a CMO for your ADC: Access Analytical and Manufacturing Platforms, Specialized Facilities, and Expertise.” Bioprocess International. 15 Oct. 2014. Web.6. Cynthia A. Challener. “Conjugation Chemistry with Highly Potent Compounds.” Pharmaceutical Technology. 2 Apr. 2012. Web.

ABOUT THE AUTHOR


> DESIGN OF EXPERIMENTS (DOE)


was able to show what the predicted opti-

mum of the multivariate conditions was,

and then verify it in the lab. This led to use

of a higher-than-expected optimal temper-

ature range on scale. Modeling of the reac-

tor system heat transfer from small scale

calorimetry experiments was then used to

establish the most effective engineering

controls, such as an automated flow meter,

to control the addition rate to maintain the

ideal temperature range. This effort trans-

lated into a 20% increase in the yield of the

key intermediate.

FOCUS ON SOLID-STATE CHEMISTRY

Knowledge of the solid-state characteris-

tics of solid small molecule APIs is crucial

to the development of their safe and effec-

tive formulated final product. Successful

and consistent oral solid dosage formula-

tions are inherently dependent upon the

physical properties and solid-state charac-

teristics of crystalline compounds.

The right-first-time approach to solid-

state chemistry has led us to broaden our

focus from primarily polymorphs to crys-

tal habits. While the polymorph of a com-

pound has an impact on the performance

of the formulated product — mostly due to

variable solubility and, therefore, bioavail-

ability — formulation performance is more

directly impacted by crystal habit. Crystal

habit may or may not be tied to polymorph,

but it will impact things such as particle

size distribution, bulk density and com-

pressibility. These are classic factors in

solid oral dosage formulation, and incon-

sistency in these API attributes can lead to

variable formulation results in things such

as tablet friability or content uniformity.

CUSTOMERS ARE INTEGRATED INTO THE GOVERNANCE PROCESS AS MUCH AS POSSIBLE, FROM THE VERY EARLIEST DEVELOPMENT STAGES THROUGH COMMERCIALIZATION.

RIGHT-FIRST-TIME INNOVATIONAPPROACH DRIVES CONTINUALINVESTMENTEfficient development of optimal routes and manufacturing processes for the production of increasingly complex small molecule APIs requires extensive expertise, advanced equipment and technology, and a right-first-time mentality. Demonstration of these capabilities has resulted in growing demand and a need for continual investment at Alcami’s Germantown, Wisconsin facility.

> BY ADAM KUJATH, ALCAMI CORPORATION

STRONG DEMAND

Despite much discussion of the growing

importance of biologics in the pharma-

ceutical industry pipeline, small molecule

drugs still account for the greatest per-

centage of drug sales and make up the

greatest percentage of drugs in develop-

ment today.1,2 As a result, the global small

molecule active pharmaceutical ingredi-

ent (API) market is expanding at a rate of

approximately 7.0% per year from 2016

to 2027 to reach a value of $279.7 billion,

according to Cooked Research Reports.3

In 2016, Mordor Intelligence estimated

the value of the global pharmaceutical con-

tract manufacturing market to be $65.1 bil-

lion, growing at a CAGR of 6.35% to reach

$94.38 billion by 2022.4 The growth in

demand for highly potent APIs (HPAPIs)

is contributing to this strong growth of

the small molecule API market. Markets

and Markets predicts that the global

HPAPI market will reach $24.09 billion by

2021, rising at a compound annual growth

rate (CAGR) of 8.5% from 2016 to 2021.5

HPAPIs are particularly challenging to

manufacture, as they require highly special-

ized facilities, equipment and personnel.

The extensive capital investment needed

to establish safe and efficient production

processes is an important factor driving

outsourcing to contract manufacturing and

development organizations (CDMOs).

Outsourcing is particularly driven by

small and mid-sized pharmaceutical com-

panies, which account for a large portion of

new drug discovery efforts. These compa-

nies have limited resources to pursue de-

velopment and commercialization of their

promising candidates. CDMOs that offer

integrated services and can tailor their

advanced technologies and supply chain

solutions to their specific customers are

needed to facilitate development and re-

duce time to market.

RIGHT-FIRST-TIME MENTALITY

Driving a predictive approach from the

start of each project, rather than remediat-

ing process issues after the fact, acceler-

ates development of optimum processes

that afford cost-effective and highly ef-

ficient production operations. At Alcami,

rather than focus on just the empirical re-

sults, we focus on the intent and purpose of

each process to understand all of the rele-

vant factors. Predicting which parameters

may impact process performance is a criti-

cal, yet often underemphasized, step in de-

velopment. We then apply a design of ex-

periments (DoE) approach, in conjunction

with techniques such as principle compo-

nent analysis, to establish the process de-

sign space. Having a predictive DoE model

allows us to identify optimal and robust

processes very early on. Often such an ap-

proach is viewed as cost and time prohibi-

tive — and thus limited to use at later pro-

cess development and commercialization

stages. However, a risk-based approach

to determine where such studies are most

value-added, coupled with our use of auto-

mated parallel reactor platforms, mean we

can execute these studies quickly and with

minimized cost implications, even in the

early clinical phases.

Alcami follows a detailed governance

process that leverages the extensive indus-

try experience of a large team of individu-

als. We tap into this collective leadership

and knowledge for each project, and each

team must present and justify its proposed

control strategy using detailed data. Con-

trol strategies are expected to be three-

pronged by including parametric controls

(e.g., chemistry-proven acceptable ranges)

overlaid with engineering/automation con-

trols (e.g., controllable ranges) and detec-

tion controls (e.g., analytical testing plan).

The level of overlap of these methods of

control allow for an effective quantifica-

tion of process performance risk. Custom-

ers are integrated into the governance

process as much as possible, from the very

earliest development stages through com-

mercialization. Any risk analysis is only

as good as the knowledge available and

the people who are conducting the study;

bringing customers in expands the infor-

mation and experience available, leading

to improved process design.

As an example, a recent customer proj-

ect involved a cryogenic reaction where

purity profile and, ultimately, yield were

known to be influenced by a number of dif-

ferent factors. Often with such reactions,

the assumption was colder was better for

purity control. However, through the use of

DoE, a predictive design space model was

able to be created, and the chemistry team


An extensive full-factorial DoE was con-

ducted in order to gain an understanding

of what crystallization conditions con-

trolled crystal habit for a specific API. It

was found that there were not only primary

interactions of cooling rate and concentra-

tion, but secondary interactions of solvent

denaturant concentration and water con-

tent that dictated the crystal growth pat-

terns. Without the use of a high-resolution

experimental design, it would not have

been possible to understand the interplay

of so many factors. Experience is key in

first establishing where to look, and the

experimental design is key in how to look.

GROWING CENTER OF EXCELLENCE

The Germantown, Wisconsin API produc-

tion facility was established in 2004, first

expanding in 2009 and again in 2013, when

a new commercial production bay contain-

ing seven reactors was added as well as the

addition of the new administrative center.

In September 2017, we formed a Center of

Excellence for API development, scale-up

and commercialization at the facility.

This right-first-time approach has al-

lowed Alcami to provide its customers with

consistent and continuously improving

results. The resulting increased demand

has been driving the need for continued in-

vestments to increase throughput and ca-

pacity, including new drying and isolation

equipment. We have also invested in the fa-

cilities and equipment needed to produce

controlled substances, and in June 2017, re-

ceived a Drug Enforcement Agency (DEA)

Bulk Manufacturer registration to comple-

ment our Analytical and Researcher reg-

istrations. We now have the capability to

develop and manufacture up to Schedule I

and II products, respectively.

Combined, these investments are part of

our commitment to provide customers with

seamless, efficient end-to-end small mole-

cule services, enabling them to execute all

parts of API development and manufactur-

ing in one US-based location. In addition,

we will be using the API Center of Excel-

lence as a platform to further advance our

approach to control strategy at each phase

of the development process, through a se-

ries of investments targeted at infrastruc-

ture, workforce, tools and technology. The

goal is to accelerate drug substance and

product development, risk quantification

and management, and the design, scale-up

and commercialization of quality manu-

facturing processes for our customers, all

from our location in Germantown.

Perhaps most exciting is the completion

of investments to expand our capability

for HPAPI manufacturing. The facility was

designed to be highly flexible, as the Ger-

mantown site is a multiproduct production

campus. Flexibility under high contain-

ment conditions is a real challenge. Our

approach was to include multiple levels of

containment within each suite to allow the

use of a mix of portable and fixed pieces

of process equipment — affording the abil-

ity to run hydrogenations, cryogenic chem-

istry, distillations and isolations. A mix

of glass-lined and Hastelloy reactors are

included to ensure the ability to handle a

broad range of chemistries. As a result, we

are able to rapidly set up a suite for many

different types of operations.

Two state-of-the-art cGMP production

suites equipped with engineering con-

trols designed to meet or beat the estab-

lished Occupational Exposure Limit (OEL)

of minimally 0.03 μg/m3 (SafeBridge® Cat-

egory 3) will be operational in Q4 2017.

Alcami now has the capability to support

projects involving highly potent com-

pounds from development through com-

mercial production, eliminating the need

for customers to transfer their projects

from one facility to another.

We are already preparing for process

validation to support the potential com-

mercial launch of an HPAPI at the site in

the new suites. Overall, the process, oper-

ational and technology enhancements Al-

cami has made across development, clini-

cal and commercial manufacturing have

increased our production capacity by

over 50%. Investments are also ongoing

to increase automation capabilities for

more efficient high-throughput reaction

REFERENCES

1. Agnes Shanley. “Stronger Pipelines And Approvals Drive Small-Molecule APIs And CMO Opportunities.” Pharm. Tech. 31 Mar. 2015. Web.2. Jim Miller. “Small-Molecule API CMOs Are Thriving.” BioPharm International 28.10 (2015): 10-12.3. Global Small Molecule API Market Research Report — Forecast to 2027. Rep. Market Research Future. Aug. 2016. Web. 4. Global Pharmaceutical Contract Manufacturing Market — Growth, Analysis, Forecast To 2022. Rep. Mordor Intelligence. Jun. 2017. Web. 5. High Potency API /HPAPI Market by Type (Innovative, Generic), Synthesis (Synthetic, Biotech (Biologic, Biosimilar)), Manufacturer (Captive, Merchant), Therapy (Oncology, Glaucoma, Hormonal Imbalance) — Global Forecast to 2021. Rep. Markets and Markets. Jan. 2017. Web.

screening, which will enable more rapid

and cost-effective use of DoE. We have

also been investing in process analyti-

cal technology, such as our new focused

beam reflectance measurement (FBRM)

probe, to allow real-time monitoring of

crystallization or milling processes and

thus enhanced tracking of crystallization

kinetics and growth and particle sizing

during full-scale manufacturing.

WELL-RECEIVED APPROACH

Having a robust development approach

and process control strategy, coupled with

state-of-the-art equipment for contain-

ment, process monitoring and automation,

positions Alcami to provide customers

with optimum synthetic routes and pro-

duction processes for their small molecule

drug substances. Customers appreciate

knowing that Alcami has a control strategy

in place across all API-related activities.

This approach is also applied across the

broader Alcami organization, thus leading

to a much stronger supply chain, ensuring

critical clinical milestones are met and

commercial supply is maintained. P

ABOUT THE AUTHORAdam Kujath Site Director, Germantown, Alcami

Adam Kujath has over 13 years of experience in API process development and operations. He is currently the Site Director for Alcami’s US API Operation in Germantown, WI, where he has been key in creating its position as a Center of Excellence. His experience as site director draws from work in operations, technical services, manufacturing resources planning and project management. Adam graduated with a degree in chemistry from Carroll University.

LinkedIn www.linkedin.com/in/adam-kujath-0704b139/ Email [email protected]

79 Days from Concept

to Clinic

Active Pharmaceutical Ingredients • Drug Product & Packaging

Development Services • Analytical Testing

www.alcaminow.com

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ONCOLOGY

PHARMASALMANAC.COM 3130 PHARMA’S ALMANAC GLOBAL PHARMACEUTICAL SUPPLY CHAIN TRENDS Q4 2017

iosimilars are defined as having

no clinically meaningful difference

from the biologics reference prod-

uct, though they are not necessarily

“interchangeable.” The legislation

encouraging the production of biosimilars

was solidified through The Patient Protec-

tion and Affordable Care Act (Affordable

Care Act) signed into action by former

President Obama in 2010. Biologics indeed

get special mention, via the Biologics Price

Competition and Innovation Act (BPCI Act),

which states that a biosimilar can only be a

biosimilar if data and trials prove the drug

is “highly similar” to a biologic drug prod-

uct already on the market.1 The act thus

explains that biologics are only allowed

minor differences and therefore must not

diverge in safety or pose any additional

risks than the original biologic.1 This act

also made the path to becoming a biosimi-

lar easier — as long as the drug is not clini-

cally different from the biologic, a biosimi-

lar is not considered its own original entity

and does not have to go through with a full

approval timeline; much like generics for

API drugs, the only standard is to meet the

requirement of equivalency and serve as a

copy of the biologic in question.2

Biosimilars by NameOf course, questions still loom. For in-

stance, how can healthcare providers keep

informed on biosimilars and recognize

when they should be substituted for the

biologic? The FDA has answered this with

their Nonproprietary Naming of Biologic

Products, which is a guidance for the in-

dustry.3 The guidance states: “the nonpro-

prietary name designated for each origina-

tor biological product, related biological

product, and biosimilar product will be a

proper name that is a combination of the

core name and a distinguishing suffix that

is devoid of meaning and composed of

four lowercase letters.” However, as of the

publish date of the guidance, interchange-

able products were still not given a suffix

format convention. The agency’s recom-

mendation for the suffix of all biologics,

whether original, related or biosimilar, is

that all follow the same set of “shoulds.”

The main takeaway of the guidance is

that the naming should be unique and not

meant to be misleading or confusing to the

user. A chief recommendation is that no

suffix can be “too similar” in either look

or name. It should not “be capable of being

mistaken for the name of a currently mar-

keted product (e.g., it should not increase

the risk of confusion or medical errors with

the product and/or other products in the

clinical setting),” nor should it “Look simi-

lar to or otherwise connote the name of the

license holder.”3

Taking this into consideration, it is clear

that the FDA is paving the way for biosimi-

lars, and that although only minor differ-

ences are allowed (which do not affect

the overall performance or efficacy of the

drug product), they must be independent in

other ways so as not to confuse the market

with being an existent product. The first

biosimilar to be approved in the US was

Zarxio (filgrastim-sndz) manufactured by

Sandoz, Inc. Zarxio can be prescribed for

the same indications as Amgen’s Neupo-

gen, which was originally licensed in 1991.4

Speaking on the breakthrough approval of

the nation’s first biosimilar, FDA Commis-

sioner Margaret A. Hamburg, M.D., noted

on March 6, 2015, “Patients and the health

care community can be confident that

biosimilar products approved by the FDA

meet the agency’s rigorous safety, efficacy

and quality standard,” and that “biosimi-

lars will provide access to important thera-

pies for patients who need them.”

Almost exactly a year following, the

agency approved the second biosimilar,

with the goal of providing more treatment

options to more people and increasing

accessibility to affordable care. Inflectra

(infliximab-dyyb), manufactured by Celltri-

on, Inc., is a biosimilar to Janssen Biotech,

Inc.’s Remicade (infliximab), which passed

through the FDA on April 5, 2016. Again,

Leah Christl, Ph.D., Associate Director for

Therapeutic Biologics at the FDA, high-

lights the fact that a biosimilar is not a rep-

lica of the biologic: “A biosimilar is not an

exact duplicate of another biologic; rather,

a biosimilar is highly similar to the refer-

ence product.”5 Driving the point home

that this is likely the future of pharma and

the way we take drugs, Christl emphasizes

the growth potential for biosimilars. “Bio-

similars are likely to create greater com-

petition in the medical marketplace,” she

notes. “This could not only increase treat-

ment options for patients but also lead to

less expensive alternatives to compara-

ble products. With an increasing number

of biosimilars on the market, consumers

may expect to get equally safe and effec-

tive treatment, but at lower costs,” says

Christl.5

B

Following a string of approvals, biosimilars are positioned to go the way of generics.

The Upward Trend of Biosimilars

No Clinically Meaningful Difference:

INNOVATION FOR QUALITY, COST& COMPETITIVE ADVANTAGE

eeping up with quality is key for the industry throughout

the supply chain. Quality must be ensured from the ear-

liest phases of development, always with an eye toward

manufacturing. It is almost taken for granted that a drug

product will be produced without any defects, and fol-

lowing all GMP regulations — often times meeting more

than one governing agency’s requirements. However,

the road to perfection in manufacturing is not necessar-

ily without issue. In spite of these challenges, quality remains the

goal — and it is with this goal in mind that innovation happens.

Innovation is driven not only by the need to improve, but also to

create difference. The drivers of innovation in pharma and bio-

tech range, though in each case manufacturers must keep an eye

toward quality. A happy byproduct of innovation is a firm competi-

tive advantage. Not only does innovation improve process, quality

and patient outcomes, it shows a company that can demonstrate

effective innovation will likely outperform other organizations.

There are endless developments happening in all phases of the

industry — and these developments are more than exciting. The

industry is on a precipice, and from now until the next decade is

when these advances may finally launch. From immuno-oncology

to wearable devices in clinical trials and even an entirely new way

to manufacture, we are more than on the verge — we are dangling

over the future’s edge.

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I N N O V A T I O N F E A T U R E

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ADCs The Monoclonal Antibody

Market Is ThrivingThe development of monoclonal antibody

(mAb) drugs has had a tremendous impact

on the (bio)pharmaceutical industry since

the first mAb was commercialized in 1986.1

The ability of these biomolecules to bind

to and influence targeted cells has led not

only to safer and more effective therapies,

but medicines for previously untreated

diseases. As of November 10, 2014, some

47 mAbs had been approved in the US or

Europe.1 In 2017, there are 58 mAbs on the

market2 and more than 50 mAb candidates

being evaluated in late-stage clinical stud-

ies, with at least six to nine new products

expected to receive approval each year for

the near future.3

Rapid growth of the market is clearly

occurring. Grand View Research predicts

the global market for mAbs will expand

from $85.4 billion in 2015 to $138.6 billion

by 2024.4 Human-based mAbs, in particu-

lar, will grow at a high annual growth rate.

Technology for the commercial production

of mAbs is also improving, leading to accel-

erated development.

References

1. Information On Biosimilars. U.S. Food and Drug Administration. 10 Mar. 2010. Web. 2. From Our Perspective: Biosimilar Product Labeling. U.S. Food and Drug Administration. 11 Jan. 2017. Web. 3. Nonproprietary Naming Of Biological Products: Guidance For Industry. U.S. Food and Drug Administration. Jan. 2017. Web. 4. FDA approves First Biosimilar Product Zarxio. U.S. Food and Drug Administration. 6 Mar. 2015. Web. 5. Biosimilars: More Treatment Options Are On The Way. U.S. Food and Drug Administration. 28 Aug. 2017. Web. 6. Zachary Brennan. “US Supreme Court: No Six-Month Wait For Biosimilars After FDA Approval.” Regulatory Affairs Professionals Society. 12 Jun. 2017. Web. 7. Sandoz Inc. V. Amgen Inc. et al. Supreme Court Of The United States. 12 Jun. 2017. Web. 8. Damian McNamara. “Supreme Court Ruling On Biosimilars Will Lower Drug Costs.” Medscape. 17 Aug. 2017. Web.9. “Delivering On The Potential Of Biosimilar Medicines: The Role Of Functioning Competitive Markets.” IMS Institute For Healthcare Informatics. Mar. 2016. Web. 10. Simon Wentworth. “Are We On The Verge Of A Biosimilars Breakthrough In The USA?” The Pharma Letter. 22 Aug. 2017. Web. 11. Zachary Brennan. “FDA: Interchangeable Biosimilar Approvals Expected Within 2 Years.” Regulatory Affairs Professionals Society. 26 Jun. 2017. Web.

tract Development and Manufacturing Sur-

vey, 33% of respondents whose business

is engaged in the development of biolog-

ics are involved in the manufacture of

biosimilars. Of those, 17% outsource bio-

similar production to contract service

providers. The US is behind the EU curve

when it comes to biosimilars, and may

need to go into overdrive during the com-

ing years in order to make up for lost time.

There are 32 biosimilar products approved

for use in patients in Europe, based off of

12 biologics, as compared to the five in the

US.10 Furthering the trend, interchangable

biosimilars are expected to be produced

within the next two years. 11

Innovate or DieIt’s an exciting time for the industry, and

the reason for that excitement is mainly

innovation. Whether the driver is cost,

quality or just trying to find a solution that

doesn’t yet exist, the marketplace stands

to benefit from an influx of new ideas,

better answers and improved processes.

The firm that is able to capture this inno-

vation wave will not only come out ahead

— a byproduct of innovation is competitive

advantage — but will also be able to claim

a greater social good, as these lifesaving

therapies reach the table almost as soon

as they are approved. Keeping this in

mind, it’s best to get out of the way of inno-

vation, for there is little that can be done

to stop it. P

predicts that the global biologic medi-

cines market will exceed $390 billion by

2020 and account for up to 28% by value

of the global market for pharmaceuticals.9

This growth is predicted to create more

choice and greater treatment options.

Also according to QuintilesIMS, “Over the

period 2016-2020, some 225 new active

substances (NAS) are expected to come to

market globally.” Of these, based on trends

over the last 20 years, approximately 30%

will be biologic in nature.9 Spending has

no sign of slowing down, either. The firm

predicts a highly steady growth rate, with

“global spending on medicines expected

to grow at a compound annual growth rate

of 4%-7% over the same period, to reach

up to US $1,430 billion” by 2020.

A key to sustaining the growth of the bi-

osimilar market is the embracing of com-

petition, facilitated by government. There

are 50 distinct biosimilars poised to enter

the market within the next five years, and

these are positioned to create a great deal

of competition in the marketplace.9 How-

ever, for patients to fully reap the benefits

of biosimilars, the competitive landscape

must be embraced as part of the culture

of innovation, progress and development.

The challenge of biosimilars coming to

market is directly related to government,

as the national healthcare costs will be re-

duced. QuintilesIMS projects the United

States, Germany, France, Italy, Britain and

Spain will save as much as $110 billion by

2020, approximately, because of biosimi-

lars entering the mainstream.9

Ready to ManufactureAccording to the 2017 Nice Insight Con-

Biosimilars Ease into the Pharmacy It is likely that biosimilars will not only fill

a gap in the healthcare system as being a

lower cost alternative, but that as more

drugs shift toward patent expiry territory,

these will be considered go-to drugs. Not

only will that increase competition in the

market, but this competition is sure to fuel

greater innovations. In a Supreme Court

decision on June 12, 2017 (just over two

years from the passing of the first biosimi-

lar in the US), a unanimous decision was

reached to confirm that manufacturers

do not need to wait the typical six months

after FDA approval to begin manufacture.6

In the opinion, Justice Clarence Thomas

wrote, “An applicant may provide notice of

commercial marketing before obtaining a

license.”7 This has the potential to speed

up the process of patient accessibility

greatly; the waiting time from approval to

manufacture becomes nil with this new

measure. The ruling shook up the industry,

with mixed opinions coming from all sides;

however, Stephen Hanauer, MD, Professor

of Medicine at Northwestern University in

Chicago, summed up the money-making

potential of the decision for the industry,

noting: “Six months of marketing is a lot of

money for a billion-dollar drug,” he contin-

ued. “This will affect the economics of the

pharmaceutical industry.”8

The potential for capital is further

clarified when looking at the market for

biosimilars as a whole — namely, the pro-

jected growth and product value over the

next ten years. According to health infor-

mation technologies and research firm

QuintilesIMS, this space is poised for in-

credible growth in the US. The company

Next-generation antibody therapeutics are designed to provide improved specificity, efficacy and safety when compared to conventional monoclonal antibodies.


The Five Biosimilars Approved by the FDA

Biosimilar Biosimilar Manufacturer

Originator Biologic

Biologic Manufacturer

Amjevita (adalimumab-atto) Amgen Humira AbbVie

Erelzi (etanercept-szzs) Sandoz Enbrel Amgen

Inflectra (infliximab-dyyb) Pfizer/Celltrion Remicade Johnson & Johnson

Renflexis (infliximab-abda) Samsung Bioepis Remicade Johnson & Johnson

Zarxio (filgrastim-sndz) Sandoz Neupogen Amgen

Moving Beyond Monoclonal Antibodies

References

1. Dawn M. Ecker, Susan D. Jones, Howard L. Levine. “The Therapeutic Monoclonal Antibody Market.” MAbs 7.1 (2015): 9-14. Web.2. Junho Chung. “Special Issue On Therapeutic Antibodies And Biopharmaceuticals.” Experimental & Molecular Medicine 49.3 (2017): e304. Web.3. Janice M. Reichert. “Antibodies To Watch In 2017.” MAbs 9.2 (2017): 167-181. Web.4. “Monoclonal Antibodies (mAbs) Market Size Worth $138.6 Billion By 2024.” Grand View Research. Nov. 2016. Web.5. Cynthia A. Challener. “Witnessing Major Growth In Next-Generation Antibodies.” BioPharm International 30.4 (2017): 14–19. Web.6. Next Generation Antibody Therapies Market Forecast 2016-2026. Biosimilar Development. 11 May 2016. Web. 7. Fc Protein And Glycoengineered Antibodies Market (2nd Edition), 2016 – 2026. Rep. Roots Analysis. 31 Mar. 2016. Web.8. “Next-Generattion Antibodies.” Janssen. Web.9. Global Antibody Drug Conjugates (ADC) Market — Analysis By Drugs (Adcetris, Kadcyla), Pipeline Drugs, Regulations: Opportunities and Forecasts (2017-2022). Rep. Azoth Analytics. Mar. 2017. Web.10. Alain Beck, Liliane Goetsch, Charles Dumontet, Nathalie Corvaia. “Strategies And Challenges For The Next Generation Of Antibody–Drug Conjugates.” Nature Reviews Drug Discovery 16 (2017): 315-337. Web. 11. Bispecific Antibodies Close in on Cancer: Plotting Molecular Pincer Movements, Denying Cancer Room to Maneuver. Genetic Engineering News. 27 Feb. 2017. Web. 12. Bispecific Antibody Therapeutics Market, 2014 – 2024. Rep. Roots Analysis. 2 Dec. 2014. Web.13. “Bispecific Antibodies Market Industry Insights, Trends, Outlook, And Opportunity Analysis, 2016–2024.” Coherent Market Insights. 23 Mar. 2017. Web.

ple of a large pharma company, is develop-

ing immunoglobulins (IgGs) with hyper-Fc

activity for targeting pathogens, tumor

cells and protease-resistant IgGs with a

variety of potent Fc activities for targeting

pathogens, the highly protease-rich tumor

microenvironment and inflamed tissues

that are high in protease activity.8

Next-Gen Antibody-Drug (and Other) Conjugates Show Great PromiseADCs comprise a monoclonal antibody

linked to a highly potent small molecule

drug, allowing highly targeted delivery of

toxic payloads to specific cells. The abil-

ity of ADCs to treat oncologic indications

with minimal side effects has attracted

significant attention, and today ADCs

are also being investigated for many non-

cancer indications. For these reasons,

Azoth Analytics predicts the global ADC

market will expand at a CAGR of nearly

22% from 2017-2022.9

Two second-generation ADCs — Kad-

cyla® (ado-trastuzumab emtansine from

Genentech) and Adcetris® (brentuximab

vedotin from Seattle Genetics) — with

higher levels of conjugation, greater ho-

mogeneity and improved linker stability

have already been approved and proven

to be highly successful, and there are

approximately 60 other ADCs in devel-

opment in 2017.10 Third-generation ADCs

under development are being designed

to target more effective antigens and use

more effective small molecule cytotox-

ics, yet present reduced toxicity issues,

incorporate new linker chemistries and

function via new mechanisms of action.10

crystallizable (Fc), or back-end, region,

which is responsible for interaction with

the immune system.7 Other approaches

include protein engineering and isotype

chimerism. All three methods are in-

tended to increase stability by extending

half-life and improve the efficacy/po-

tency of traditional mAbs by increasing

their antibody-dependent cell-mediated

cytotoxicity (ADCC), complement-depen-

dent cytotoxicity (CDC) and/or antibody-

dependent phagocytosis (ADCP) activi-

ties.7 In addition to the development of

novel next-generation antibodies, engi-

neered antibodies are also being investi-

gated as biobetters.

Roots Analysis predicts that glycoen-

gineered antibodies will account for 84%

of the antibody market by 2010, while Fc-

protein engineering antibodies will ac-

count for 56% of the market by 2026. The

market research firm also anticipates

that Atezolizumab from Roche and Dur-

valumab from AstraZeneca/MedImmune

will be blockbusters.7 Overall, the engi-

neered antibodies market will expand at

a compound annual growth rate (CAGR) of

40% between 2016 and 2026.7

Most engineered antibodies under de-

velopment target oncology indications,

but some are intended for the treatment

of other indications, including asthma,

chronic obstructive pulmonary disease,

neuromyelitis optica, ulcerative colitis

and hemolytic disease in newborns.7 Over

70 products are either marketed or in pre-

clinical/clinical development.7 Examples

of companies developing engineered an-

tibodies include MacroGenics, arGEN-X,

Celldex Therapeutics, Clovis Oncology,

Five Prime Therapeutics Inc., Genmab,

Immune Design, MorphoSys, TG Thera-

peutics and Zymeworks, as well as most

major pharma firms (Amgen, AstraZen-

eca/MedImmune, Boehringer Ingelheim,

Roche/Genentech, Janssen, etc.). Other

firms have developed proprietary glyco-

engineering technologies, including Bio-

Wa (POTELLIGENT®), Glycart (GlycoMAb),

Glycotope (GlycoExpress™), ProBioGen

(GlymaxX®) and Xencor (XmAb Fc).

MacroGenics, Inc., according to Presi-

dent, CEO and Director Scott Koenig, is

one company pursuing protein engineer-

ing for the production of modified mAbs.

This firm substitutes carefully selected

amino acids in the Fc region to afford

desired activities.5 Janssen, as an exam-

the potential for new mechanisms of ac-

tion, allowing access to different targets

and multiple targeting within the same

molecule, according to Mike Riley, Vice

President and General Manager at Catal-

ent Biologics.5

In some cases, synergistic effects lead

to better performance in one molecule

than can be achieved using two separate

mAbs, according to Tony de Fougerolles,

Chief Scientific Officer with Ablynx. He

also notes that unexpected biological

functionality can be revealed and uti-

lized that is not accessible with mAbs.5

Of course, each next-generation antibody

technology must be evaluated on its own

merit and offers its own set of advantages

and disadvantages. Some of these tech-

nologies involve smaller changes to mAb

structures for improved performance, but

with no significant changes in functional-

ity, while others involve new modes of ac-

tion but consequently carry greater risk

and require proof of viability and com-

mercial feasibility.

Taking Small Steps with Engineered AntibodiesEngineered antibodies consist of mAbs

that have been modified in some way.

For instance, in the approved drugs Ga-

zyva® (obinutuzumab from Genentech)

and Poteligeo® (mogamulizumab from

Kyowa Hakko Kirin Co., Ltd.), glycoengi-

neering was used to modify the fragment

Next-Gen Antibodies with Improved Performance Monoclonal antibodies do have their limi-

tations, however, and many biopharma-

ceutical companies are developing next-

generation antibodies designed to over-

come them. Not only are they seeking to

improve the safety, specificity and potency

of mAbs, they are looking to develop anti-

bodies that are more manufacturable.5

Their potential to offer improved perfor-

mance has attracted the attention of most

biopharmaceutical companies. As a result,

Visiongain estimates the global market

for next-generation antibodies, including

engineered antibodies, antibody-drug con-

jugates (ADCs), bispecific and multispe-

cific antibodies, antibody fragments and

antibody-like proteins (ALPs), as well as

biosimilar antibodies, will reach $11.6 bil-

lion in 2020.6 A few products have already

received approval.

While many next-generation antibod-

ies are designed to treat various types of

cancer, there are new candidates being

developed for other indications ranging

from infectious diseases to central ner-

vous system disorders. Next-gen antibod-

ies have the potential to treat any type of

disease, according to Andrew Chan, Se-

nior Vice President of Research Biology

at Genentech.5 The new modalities being

incorporated into next-gen antibodies

not only offer improved performance over

their monoclonal counterparts, they offer

The Potential of Bispecific AntibodiesAmong the different types of next-gen an-

tibodies, bispecific antibodies, along with

ADCs, perhaps have the most potential for

commercial success. The first trifunction-

al antibody (Removab®, catumaxomab from

Fresenius Biotech and TRION Pharma) was

approved in Europe in 2009. The bispecif-

ic antibody Blincyto® (blinatumomab from

Amgen) was granted conditional marketing

authorization in the EU in November 2015

and received FDA approval in July 2017.

Since December 2014, more than 120 bi-

specific molecules have entered into clini-

cal development.11 Most target cancer in-

dications, but some bispecific antibodies

are in development for non-oncological

diseases, including rheumatoid arthritis,

respiratory diseases and autoimmune dis-

eases. Roots Analysis predicts the global

market for bispecific antibodies will reach

a value of $5.8 billion by 2024.12

As of 2015, over 60 different bispecific

formats had been developed,13 such as

biXAbs® (Biomunex Pharmaceuticals), Cross-

Mabs® and DutaMabs™ (Roche/Genentech),

nanobodies (Ablynx), tandem diabodies

(TandAb, Affimed), bispecific T-cell engag-

er antibodies (BiTE®, Amgen), dual-variable-

domain immunoglobulins (DVD-Igs™,

Abbvie), Triomab® (TRION Pharma) and

dual-affinity retargeting (DART®) technol-

ogy (MacroGenics).

Bispecific and multispecific antibod-

ies are effective because they combine

two (or more) specificities for targeting

within one molecule. As a result, one

antibody-like molecule can bind two (or

The ability of ADCs to treat oncologic indications with minimal side effects has attracted significant attention, and today ADCs are also being investigated for many non-cancer indications.


more) antigens on a single or multiple

cells. They can be produced in many dif-

ferent ways and are believed to provide a

cost-effective means for accessing novel

mechanisms of action for addressing un-

met medical needs.11 For these reasons

they should have a broad range of clinical

applications, according to Paul Carter,

Senior Director and Staff Scientist for

Antibody Engineering at Genentech.5

Challenges to OvercomeAlthough there have been a handful of

next-generation antibodies approved,

many remain in clinical development and

have yet to be proven commercially vi-

able. Because these antibodies are gener-

ally more complex than mAbs, they need to

provide significant benefits compared to

traditional mAb therapies. The greater the

complexity, the greater the challenges for

development and large-scale manufactur-

ing; it is essential, according to Koening,

to demonstrate both efficacy/performance

and manufacturability.5

Managing the very high potency of many

next-generation antibodies during both

production and delivery is another issue.

More sensitive analytical techniques are

needed to detect the low levels of active

drug substance for characterization and

quality determinations. The high potency

may, however, allow the use of new, advan-

tageous delivery systems not possible with

conventional mAbs. Developing safe, con-

venient and effective delivery systems that

encourage medication adherence is a top

priority in the industry today.5 P

$85.4 B2015

2024$138.6 B

Source: Grand View Research

GLOBAL MARKET FOR mAbs

In 2017, there are 58 mAbs on the market and more than 50 mAb candidates being evaluated in late-stage clinical studies, with at least six to nine new products expected to receive approval each year for the near future.

R D&

References

1. Steve Kuehn. “Pharma’s Renaissance Continues.” Pharma’s Almanac. 1 Apr. 2016. Web. 2. Devin Bean. “Where Will Profit Be? The Threat And Opportunity Of Pharmaceutical Commoditization.” Christensen Institute Blog. 10 Oct. 2013. Web.3. Equipment — 2017 Nice Insight Pharmaceutical Survey.4. David Torrone. “Pharma’s Great Automation Migration.” Pharmaceutical Manufacturing. 4 May 2017. Web.5. Stephanie Neil. “The New Pharma Factory.” Automation World. 11 Feb. 2016. Web. 6. Bill Lydon. “Automation And Control Trends In 2016.” Automation. 22 Feb. 2016. Web. 7. “Manufacturing Vision Study.” Zebra. 2017. Web. 8. Dassault Systèmes. “Leverage The Internet Of Things (Iot) Within The Laboratory.” Bioprocess Online. Web.9. Karenann Terrell Appointed Chief Digital & Technology Officer, GSK. GSK. 25 Jul. 2017. Web.10. Carrie Cao. “Flow Chemistry: Pathway For Continuous API Manufacturing.” Pharma’s Almanac. 1 Jun. 2017. Web.11. Marcus Baumann, Ian R. Baxendale. “The Synthesis Of Active Pharmaceutical Ingredients (Apis) Using Continuous Flow Chemistry.” Beilstein Journal Of Organic Chemistry 11 (2015): 1194-1219. Web.12. Chinmay A. Shukla, Amol A. Kulkarni. “Automating Multistep Flow Synthesis: Approach And Challenges In Integrating Chemistry, Machines And Logic.” Beilstein Journal Of Organic Chemistry 13 (2017): 960-987. Web.

“kitchen” blending and mixing batch af-

ter batch, with operators manually mov-

ing the process along in bins and marking

their progress on paper charts. Over the

last three decades or so, most small mol-

ecule drug manufacturers have come to

understand that this is not a sustainable

strategy and are moving faster than ever

to upgrade capacity, investing in automa-

tion at all levels to meet business priori-

ties and external expectations.

The 2017 Nice Insight Pharmaceutical

Equipment Survey queried nearly 600

highly qualified pharmaceutical industry

professionals from 90 companies involved

in specifying and purchasing new systems

and technology.3 Reflecting noted trends,

equipment purchasing budgets continue

to rise with a majority (73%) reporting an

increase to their annual equipment pur-

chasing budgets from 2014 to 2016, with

most (48%) responding that they oversee

clinical and commercial scale in-house

manufacturing capability.

These study responses revealed that

more than half of those surveyed were in-

terested in purchasing equipment, and of

those, 41% indicated interest in purchas-

ing process automation software and 39%

favored computer/automation systems. An-

other 36% are seeking manufacturing ex-

ecution system (MES) software, 35% have

indicated they were interested in process

simulation and systems validation soft-

ware, while 34% chose computer-integrat-

ed manufacturing software as a technology

of interest.

Toward Industry 4.0 and Smarter ManufacturingAs demonstrated by capital spending

trends, the acceptance and integration of

advanced manufacturing and data man-

agement technology is becoming more

pervasive, and is also accelerating.4 Inte-

grations and migrations are now practical-

ly standard, engineered and implemented

by some of the world’s most established au-

tomation technology vendors.5 Emerson,

Festo, Rockwell Automation and Siemens,

as well as allied engineering firms, are now

routinely delivering an array of advanced

digital, networked technologies — all driv-

ing process and production to the future,

now referred to as the fourth industrial

revolution or “Industry 4.0.”

In the world of “Industry 4.0,” companies

deploy networked, complementary tech-

nologies to facilitate information and data

sharing among corporate management,

lthough biopharmaceuticals have

attracted quite the limelight,

small molecule drug developers

still dominate. These developers

are pursuing a number of product

and R&D manufacturing strategies — from

introducing more sophisticated formula-

tions, specializing in active pharmaceu-

tical ingredients (APIs) and diversifying

global product portfolios, to combining

products, innovating new drug delivery

platforms and more.1

As drugs of all types become more

commoditized, there is a downward pres-

sure on prices as well.2 This socioeco-

nomic trend has put the pressure on drug

manufacturers to drive out internal costs

while guaranteeing error-free quality. To

achieve this operational balance, many

are turning to advanced manufacturing

techniques and, specifically, the applica-

tion of automation.

Automating the Kitchen For much of its history, the industry relied

on dedicated processing capacity that (in

simplistic terms) mimicked lab process

but was “super-sized” to a scale that could

meet production volumes. This could

be visualized as a giant stainless steel

The evolution of automation, sensing technologies, instrumentation and wireless controls, combined with faster computers and data paths, allows for a much more reliable integration of hardware and software.

operational segments, facilities and busi-

ness units, while machines and devices

share operating data and other informa-

tion via the Industrial Internet of Things

(IIoT) within the Cloud.6 Central to every-

thing is the pursuit of quality, and with it

the support of growth and financial health

for the organization. Zebra Technologies,

known for the bar code, surveyed some

1,100 professionals across prominent man-

ufacturing sectors — including pharmaceu-

tical and life sciences — to find out how

fast these concepts and strategies were

being adopted by companies.7

Zebra’s “2017 Manufacturing Vision

Study” found manufacturers moving quick-

ly to join Industry 4.0, and that the instant

access to data that comes with automa-

tion is essential to smooth, seamless op-

erations. “Importantly,” said Zebra’s study,

“data gives suppliers the ability to antici-

pate the needs of their customers,” better

manage risks and identify and eliminate

points of failure. “In fact,” it continued,

“50 percent of respondents stated that im-

proving their ability to adjust to fluctuating

market demands is one of their top busi-

ness growth strategies.”

In a recent whitepaper, lab systems soft-

ware developer Dassault Systèmes BIOVIA

described the benefits of Industry 4.0 and

the “Internet of Laboratory Things” (IoLT),

and concluded that one of the better ways

to deal with 21 CFR Part 11 is to be proactive

compliance-wise.8 According to the white-

paper, “connecting both equipment and

systems to the network is the most obvious

point to address, as a lack of integration

leads to manual steps in the process — and

therefore a higher likelihood of error and

increased compliance risk.” Accurate data

capture is key, said Dassault, as an IoLT

operation connects everything, facilitating

the automatic detection of samples using

barcodes and radio frequency identifica-

tion. Lastly, with data accurately captured

and compiled, managers pay attention to

using that data more effectively in order to

make better business decisions.

Current Projects, Future BenefitsIntegrating automation and process con-

trol into manufacturing operations is also

markedly less risky than the alternative.

Regulators are openly supporting the mi-

gration to “Industry 4.0” manufacturing

environments that demonstrate compli-

ance and sustain quality. However, the

adoption rates of advanced automation

and manufacturing IT are as varied as the

number of companies in the space.

A Continuous Future Enabled by AutomationChemical synthesis in oral solid dose man-

ufacturing has traditionally been batch-

flow oriented, but that is shifting as drug

manufacturers explore continuous flow

chemistry as the preferred way to process

commercial quantities of small molecule

API and solid dose medications.10 A recent

paper published in the Beilstein Journal

of Organic Chemistry reviewed the body

of academic study on continuous manu-

facturing in pharma processing, and con-

cluded that multiple-step flow chemistry

has matured from an innovative concept to

a “powerful and widely applicable tool box

enabling the efficient multistep synthesis

of numerous active pharmaceutical in-

gredients.”11 The study noted that current

estimates suggest industrial applications

of continuous manufacture of pharmaceu-

ticals will “grow from 5% to 30% over the

next few years.” That is quite a spread, but

there is mounting evidence that continuous

flow manufacturing is ready for prime time.

Automation’s role in controlling con-

tinuous flow chemical synthesis — and that

includes process analytical technologies

— is evident and, according to another fo-

cused study published in the same journal,

essential in converting laboratory-scale

multistep flow synthesis into industrial/

commercial processes.12 When compared

to conventional batch processes, authors

A


Call it the automation of everything — a hands-off approach will permeate supply chains in the near future.

Pharma’s Automation Index on the Rise

of “Automating multistep flow synthesis:

approach and challenges in integrating

chemistry, machines and logic” agree that

flow processes make the most logical case

for implementing automation. To date,

and with few exceptions, “automation in

synthesis has always been interpreted as

auto-sampling, in-line monitoring, and

self-optimization systems. Auto-sampling

and in-line monitoring of process variables

like temperature, concentration, pressure,

pH, etc. will not only improve the produc-

tivity of researchers but also improve the

reproducibility of the experiments.” Varia-

tion is also much more transparent — with a

better understanding of variation, process

engineers can sustainably control quality

and reproducibility.

The evolution of automation, sensing

technologies, instrumentation and wire-

less controls, combined with faster com-

puters and data paths, allows for a much

more reliable integration of hardware and

software. This technical environment has

reached a stage where there is no threat

of ambiguity; process engineers are no

longer relying on data that may be linked

to human error, and chemists can lean on

machine-based synthesis. In perhaps the

greatest case for automation yet, a process

free from error is one way to ensure opera-

tional quality, and push drug development

to a further frontier. P


UBIQUITOUS PHYSIOLOGICAL INVOLVEMENT

Potassium channels are membrane pro-

teins that form pores in cell membranes

through which potassium ions (K+) flow.

They are present in nearly all types of

cells and involved in most physiological

functions. There are in excess of 90 dif-

ferent types of potassium channels, which

open and close in response to a range of

signals (change in voltage, pH, ATP sup-

ply, intracellular calcium levels, etc.).

Potassium channels activated by chang-

es in cell membrane voltage (voltage-

dependent potassium (Kv) channels) com-

prise the largest group. In humans, 40

genes have been identified that encode

Kv channel subunits that can form homo-

and hetero-multimeric channels, which

are divided into 12 subfamilies.

The opening of potassium channels

leads to the exit of K+ from cells and a drop

in the resting membrane potential. As a

result, K+ channels modulate nerve and

muscle excitability, neurotransmitter and

hormone release, water and electrolyte

transport, cell proliferation and apoptosis,

etc. Improperly functioning K+ channels

have been associated with a number of

diseases, including neurological and

cardiovascular disorders, cancer, immune

and metabolic diseases. Specific examples

include epilepsy, diabetes, rheumatoid

arthritis and multiple sclerosis (MS).

Several currently marketed drugs tar-

get potassium channels. For example,

sulfonylurea drugs like Gliburide inhibit

the Kir6 (KATP) class of K+ channels and

have proven to be effective treatments

for type 2 diabetes. The Kv inhibitor Dal-

fampridine (4-aminopyridine) has been

clinically approved for the treatment of

MS and the Kv7 activator Ezogabine (Reti-

gabine) has been approved for treatment

of epilepsy. Other K+ channel modulators

are in late-stage preclinical development

and are undergoing clinical trials for the

treatment of diseases such as hyperten-

sion and psoriasis.

SELECTIVITY IS KEY

Despite their importance, ion channels,

and potassium channels in particular, have

proved to be challenging drug discovery

targets. The ubiquity of K+ channels makes

it important to develop highly selective

agents. For example, potassium channels

belonging to the Kv7 family can be found in

the heart and brain, where they play differ-

ent roles in nerve excitability and cardiac

muscle contractility. Targeting specific

Kv7 channels in the brain to treat epilepsy,

while avoiding modulation of Kv7 channels

expressed in the heart, is critical to avoid

unwanted cardiac toxicity. Even within

the brain there are subtypes of Kv7 chan-

nels (i.e., Kv7.2/7.3 vs Kv7.3/7.5, Kv7.4), which

potentially play different roles in disease

and physiology, thus making subtype selec-

tive modulators of neuronal Kv7 channels

desirable as drug development candidates.

ICAGEN’S APPROACH

Recognizing that specificity is important

for K+ channel modulating drug candidates

to be safe and efficacious, Icagen focuses

on achieving selectivity early in the pro-

cess. Our drug-discovery strategies are

specifically designed to increase the like-

lihood of finding selective modulators that

can be developed into successful drugs.

Our approach has involved cloning

much of the ion channel genome in order

to be able to generate a wide range of

cell reagents that express many different

channel classes, both human and spe-

cies orthologues. In addition, we utilize

continually evolving state-of-the-art elec-

trophysiology and fluorescence assay

platforms for the screening and charac-

terization of agents, not only against chan-

nel members in the same family, but also

other ion channels, enabling both target

and off-target activity evaluation. We also

regularly employ molecular biology to

construct channel chimeras and mutants,

which has enabled the identification of

previously unknown drug binding sites on

ion channels. Such knowledge of the corre-

lation between binding site locations and

enhanced selectivity can be applied dur-

ing the development of other candidates

for ion channel targets, and expands our

ability to exploit potential interactions.

APPLYING ADVANCED

CELLULAR TECHNOLOGIES

In combination with the platform approach

described above, Icagen has also employed

human induced Pluripotent Stem Cells

(iPSC) as part of its integrated drug

candidate development progression. The

use of human tissues in drug development

is important because it has been shown

that the results obtained using animal

tissues are not always a good indication

of the drug’s performance in patients.

Human iPS cells can be converted into a

wide variety of cell types, including neu-

rons and cardiac muscle, which allows for

evaluation of drug candidates on actual

human tissue. Furthermore, iPS cells can

be obtained from human subjects carrying

disease-associated genetic variants, which

has opened up opportunities to assess not

only the impact of the mutation on cell

function but also drug candidate effects.

Thus drug candidate characterization is

not limited to healthy human cells, but also

to those carrying rare ion channel muta-

tions observed in <1% of the population, as

well as those present in a much larger per-

centage of the population. For example,

we are able to determine if there are differ-

ences in the susceptibility for epilepsy or

sensitivity to pain related to the presence

of variants. This approach falls in line with

the growing interest in precision/personal-

ized medicine.

A LOOK AT Kv7 (KCNQ) MODULATORS

A good example of Icagen’s utilization

of integrated platform of technologies,

including human iPS cell-derived neurons,

can be found in our work developing acti-

vators of the Kv7 family of voltage-gated

potassium channels. Genetic variants of

these voltage-dependent ion channels,

which are involved in membrane potential

stabilization, action potential repolariza-

tion and modulation of neuronal burst-

ing patterns, are linked to various forms

of early onset epilepsies such as benign

familial neonatal convulsions (BFNC).

The Kv7 family consists of five members

that generally are closed in the resting

state and open in response to depolariza-

tion of the cell membrane, due to excit-

atory synaptic inputs or by action poten-

tials. The subunits Kv7.2 through Kv7.5

are most highly expressed in the nervous

system, with mutation of Kv7.2 and Kv7.3

being genetically linked most frequently

to epilepsy. When activated, Kv7 channels

quiet neurons, making it more difficult to

achieve electrical excitability in the brain.

Potassium channels are highly attractive as targets for the development of novel therapeutics. Their diversity and ubiquity, however, combined with a lack of detailed structural and functional insight, pose challenges for the development of selective drug candidates. Combining a multi-platform approach with advanced cell technology is helping to overcome some of these challenges. Advances in relevant high-throughput electrophysiology technologies are opening up opportunities for greater success.

DEVELOPING TARGETED POTASSIUM CHANNEL OPENERS FOR CNS-RELATED THERAPEUTICS

> Kv7 CHANNEL MODULATORS

> BY DOUGLAS KRAFTE, Ph.D., NEIL CASTLE, Ph.D. AND AARON GERLACH, Ph.D., ICAGEN, INC.

The key to controlling seizures is to tune

back neuronal excitability to the appro-

priate level.

Most current drugs for the treatment

of epilepsy lack selectivity and thus have

a narrow therapeutic index. Unlike Kv7.2-

7.5, the Kv7.1 channel is found in the heart

and other tissues, but not in the nervous

system; as such, it is the most structur-

ally related liability target. There are mul-

tiple rare disease versions of genetically

acquired epilepsy that are related to the

loss of Kv7 channel function.

DEVELOPING SUBTYPE SELECTIVE

CHANNEL OPENERS

Retigabine was the first Kv7.x activator to

be developed for treatment of epilepsy. It

functions as a pan activator of all Kv7 chan-

nel variants (Kv7.2/7.3, Kv7.3/7.5, Kv7.4, etc.)

in the CNS. Current genetic information

indicates that Kv7.2/7.3 channels are most

commonly associated with hereditary

epilepsy, and thus selective activation of

this member of the Kv7 family of potas-

sium channels may provide advantages

over pan activators. For example, Kv7.4

plays an important role in auditory func-

tion and an activator may lead to unwanted

side effects. Thus, selective Kv7.2/7.3 acti-

vators may have the advantage of a poten-

tially lower side-effect profile.

Icagen was the first company to identify

and develop subtype selective Kv7.2/7.3

activators. This was achieved by identify-

ing drug candidates that interact with a

previously unknown binding site on the

voltage sensor of Kv7.x channels. This

class of agents, exemplified by ICA-27243

and ICA-69673, were able to distinguish

between Kv7.2/7.3 and Kv7.3/Kv7.5 channel

subtypes while also being selective over

Kv7.4 and the cardiac Kv7.1 family mem-

bers. ICA-69673 advanced to human clin-

ical trials; however, a non-target-related

toxicological profile prevented further


development. Nonetheless, the rationale

for developing selective Kv7.x activators

for treatment of neuroexcitatory disorders

like epilepsy, amyotrophic lateral sclerosis

(ALS) and pain remains.

NEXT STEPS

While Retigabine is currently marketed to

treat epilepsy, it is not widely used, pos-

sibly due to its side-effect profile. This

inadequacy highlights the continuing

need for more selective and effective Kv7

modulators. With access to more structur-

al information on ion channels, effective

high-throughput physiology testing tech-

niques, advanced in silico predictive tools

and improved models and assays, it is now

possible to screen much larger libraries of

compounds in order to identify more selec-

tive agents with better drug-like properties.

LEVERAGING ICAGEN’S EXPERTISE

With over 20 years of experience in the

development of drug candidates target-

ing ion channels, Icagen has the tools,

expertise and experience needed to help

partnering pharmaceutical and biotech

companies achieve their drug develop-

ment objectives. In addition to having the

technology platforms to support current

drug discovery progression, Icagen scien-

tists have experience taking ion channel

drug candidates into the clinic, including

two activators of Kv7 potassium chan-

nels. Icagen also developed Senicapoc, a

selective inhibitor of the KCa3.1 calcium-

activated K+ channel that was assessed in

phase III clinical trials for the treatment

of sickle cell anemia and phase II clinical

trials for asthma, and is currently being

assessed for future clinical trial(s) for

Alzheimer’s disease. Working with large

pharma partners, Icagen scientists have

also advanced several selective sodium

channel inhibitors into clinical trials for

treatment of pain and have worked with

other companies to develop a cardiac

Kv1.5 inhibitor for treatment of atrial

arrhythmias, a calcium-activated potas-

sium channel modulator for the treat-

ment of memory and learning disorders,

and Kir6 (KATP) channel openers for the

treatment of urinary incontinence. We

are eager to apply our experience in the

identification and development of ion

channel modulators to aid current and

future internal and client-sponsored

drug development programs. P

Aaron Gerlach, Ph.D. Director of Business Development, Icagen, Inc.

Aaron Gerlach works to grow Icagen’s business from a scientific perspective, including the development of scientific plans and project leadership for collaborators. Dr. Gerlach previously led multiple ion channel-focused projects at Icagen and within Pfizer, including the development of KCNQ small molecules for the treatment of drug-resistant epilepsy.

LinkedIn www.linkedin.com/in/aaron-gerlach-5279002/ Email [email protected]

ABOUT THE AUTHORS

Doug Krafte, Ph.D. Chief Scientific Officer, Icagen, Inc.

Doug Krafte is currently the Chief Scientific Officer at Icagen, Inc. Dr. Krafte has held a variety of positions over 25 years within the pharma/biotech sectors across multiple therapeutic areas, most recently as Executive Director & Site Head for the US arm of Pfizer’s Pain & Sensory Disorders Research Unit, as well as positions at Aurora Biosciences, Boehringer Ingelheim and Sterling Winthrop.

LinkedIn www.linkedin.com/in/douglas-krafte-902a739/ Email [email protected]

Neil Castle, Ph.D. Vice President of Research, Icagen, Inc.

Neil Castle is a member of Icagen’s leadership team overseeing the company’s ion channel-related activities. Prior to reforming as an independent company in 2015, Icagen was part of Pfizer’s Neuroscience and Pain Research unit, where Dr. Castle was Director of Biology and a member of the Pain Research Unit leadership team.

LinkedIn www.linkedin.com/in/neil-castle-29a3b46/ Email [email protected]

For more information about the Rare Disease Desert Symposium and registration, visit www.icagen.com/rdds-2018.

February 26-27, 2018 | Tucson, AZIcagen proudly presents the inaugural Rare Disease Desert Symposium, a two-day conference dedicated exclusively to the early discovery of promising new therapeutics to treat rare diseases.

Join us for the Rare Disease Desert Symposium

Symposium Foundation Partners

Email us: [email protected] us at: www.icagen.com RTP: +1 919-941-5206Tucson: +1 520 544 6800

ACHIEVING EFFICIENT PHARMACEUTICAL SYNTHESIS WITH PROCESS INTENSIFICATION

> FLOW CHEMISTRY

Reducing the time, cost and environmental footprint of manufacturing processes continues to be a major driver of technology development. Process intensification for small molecule API production using flow chemistry technologies gives our clients greater opportunities to implement optimum process solutions on the commercial scale.

WHY PROCESS INTENSIFICATION

THROUGH FLOW CHEMISTRY

In the pharmaceutical industry, most

small molecule production processes are

performed in batch reactors. This technol-

ogy is robust and very well implemented

— however, it does have technical limita-

tions. These limitations have to do with

the lack of heat exchange and mixing per-

formance, which can lead to safety issues

and/or reduced yields and product quality

when scaling-up the process.

In 2009, Servier CDMO began to explore

alternative manufacturing processes for

the production of chemical APIs in order

to design processes that fit the optimum

chemistry and avoid situations where a

lack of technology would limit the industri-

alization of the best chemistry. Flow chem-

istry is one such alternative manufactur-

ing approach. In a flow process, chemicals

react continuously and the process equip-

ment is designed for very efficient mix-

ing and heat removal, allowing very rapid


> BY STÉPHANE LAURENT, SERVIER CDMO

reactions. Materials are introduced con-

tinuously and react on contact with contin-

uous removal of products, with better con-

trol of process variables and the reduced

likelihood of unwanted side reactions,

often resulting in higher selectivities and

yields, as well as simpler purification pro-

cesses. The quality robustness of industri-

al flow chemistry processes is greater as a

result; when well designed, flow reactions

are reliable and highly reproducible. Scale

up is also often easier.

Only small quantities of reagents, inter-

mediates and products are present at any

given time, and thus exposure to toxic or

energetic substances is minimized. With

this type of equipment, it is possible to

perform chemistry that cannot be imple-

mented in batch mode.

The efficiency and increased speed of

flow chemistry reactions also mean that

it is possible to downsize the equipment

needed to produce commercial-scale quan-

tities, resulting in process intensification.

Less solvent is needed and less waste is

generated, resulting in a positive environ-

mental impact. Smaller production equip-

ment can also translate to smaller plant

sizes and significant reduction of the risk

associated with doing chemistry. Capital

expenditures and operating costs are of-

ten also reduced.

FOCUS ON INNOVATIVE TECHNOLOGY

The 2009 decision to explore alternative

manufacturing technologies reflects our

focus on innovation. Our parent company,

internationally recognized pharmaceutical

firm Servier, is known as a research-based

organization aimed at fulfilling basic hu-

man needs and dedicated to the future of

healthcare. To that end, 28% of the com-

pany’s turnover each year is invested back

into primary and industrial R&D.

Process R&D is performed at Servier’s

Industrial Research Center, which com-

prises four departments and 180 employ-

ees that support the rest of the company’s

activities. The departments — Chemical

Development, Analytical Development,

Pilot Plant and Innovative Technology —

interact with one another on a regular ba-

sis. Each new client project is evaluated

to determine which areas of expertise will

be required to reach the objectives of the

project. The relevant experts work as a

team under a project manager to develop

and implement a roadmap for the project.

At Servier CDMO, our experts in flow

chemistry reside within the Innovative

Technology Department and work very

closely with experts in the Chemical De-

velopment Department. Importantly, the

Industrial Research Center is located at

Servier’s Normandy manufacturing site.

As a result, all process R&D activities

take place in close proximity to our com-

mercial operations, facilitating close col-

laboration between all groups involved in

process development and commercializa-

tion. This gives us the high level of agility

necessary to meet customer needs.

WHEN IS FLOW CHEMISTRY AN OPTION?

The decision to use flow chemistry de-

pends on a number of different factors.

Our chemical development experts are

aware of the benefits of flow chemistry

and consider the use of this technology

when designing a synthetic route during

initial development. Our flow chemistry

experts also review developed synthesis

routes to determine if process intensifica-

tion technology will be beneficial for in-

dustrialization of the chemistries used in

each step.

This evaluation starts with a review of

the chemistry on paper. For extreme re-

action conditions — temperature or pres-

sure — mixing depends on reactions, fast

chemistry that involves very reactive re-

agents or intermediates — all are poten-

tial candidates.

For instance, a reaction that must be

performed over two hours at a very low

temperature (-80 °C) because it is very exo-

thermic may be suitable for intensification

at 0°C for 15 seconds. One example is reac-

tions with reactive intermediates such as

organometallic compounds, which typical-

ly can be run at room temperature in less

than a minute, preventing degradation,

improving the yield and selectivity and


ENGAGE AN EMBEDDED CDMOWith over 27 billion units of drug product manufactured annually, Servier CDMO is the CDMO to take your project from development through commercial-scale manufacture. Applying 60 years of experience and operating out of 11 worldwide facilities, Servier CDMO has the combined knowledge, capacity and empathy to deliver products in various dosage forms, with full development and regulatory support. As an embedded CDMO with large pharmaceutical roots, we understand the importance of protecting your molecule, and will treat yours as if it’s one of our own.

GOVERNANCE BY A FOUNDATION ENSURING STABILITY & INDEPENDENCE

For more information, visit us at www.servier-cdmo.com or contact [email protected]

EMBEDDED PROTECTION FOR YOUR MOLECULE

DEVELOPMENT AND COMMERCIAL-

SCALE SOLUTIONS

The process equipment used by Servier

CDMO for its flow chemistry reactions is

based on a plug-flow or continuous stir-

ring tank design. We initially considered

microreactors but found them to have

limitations with respect to the industrial-

ization of flow chemistry reactions. The

reactors (100 to 400 mL) used for investi-

gation of flow-chemistry processes allow

for excellent mixing, rapid cooling/heat-

ing and, as importantly, careful control

of these and other process parameters.

Their design is also readily transferable

to the industrial scale (20-50 L), allowing

us to more easily commercialize optimum

processes.

We currently have one dedicated,

industrialized flow chemistry process.

The reaction is perfomed in a 50 L reac-

tor. The oxidation reaction provides a key

intermediate for an API manufactured by

Servier. The batch process was a candi-

date for process intensification because it

requires the use of a reagent that cannot

be handled safely in a batch manner. This

is also because the needed level of selec-

tivity could not be achieved under batch

conditions. Both of these concerns were

addressed by switching to a continuous

process. It is interesting to note that the

workup for this reaction is performed con-

tinuously. Approximately 200 tonnes/year

of this intermediate are produced annually.

WORKING TOWARD END-TO-END SOLUTIONS

The dream for process intensification is

to achieve end-to-end continuous manu-

facturing. Ideally, each step of a synthe-

sis route would be run using continuous

processes and linked together, such that

initial reagents are input at one end and

API is isolated at the other. Even beyond

reducing the cost. Nitration reactions are

often attractive targets for intensification

because they can be dangerous when per-

formed under batch processing conditions,

but typically proceed in high yield with sig-

nificant reduction of the hazards when run

under continuous processing conditions.

Any potential steps in a synthetic route

that have been identified as candidates

for process intensification are then per-

formed in lab-scale equipment to deter-

mine if the product can be obtained in

the desired yield and selectivity under in-

dustrializable flow chemistry conditions.

At Servier CDMO, we look for intensified

reactions to be completed in less than five

minutes. Flow chemistry reactions can

proceed for longer times (i.e., hours), but

reactions that are completed in less than

five minutes are more practical for com-

mercialization. This is because the size

of the equipment needed for the produc-

tion of commercial quantities remains

sufficiently small, to afford the econom-

ic, quality and other benefits associated

with flow chemistry.

ABOUT THE AUTHORStéphane Laurent Head of Innovative Technologies R&D, Servier CDMO

Stéphane Laurent graduated from a French chemical engineer school in 1995 and further developed his R&D skills in the United States, conducting researchs on carbene chemistry for his MSc. Stéphane joined Servier and was in charge of process industrialization for more than 15 years. Since 2014, he has been in charge of the innovative technology department that works on intensified technologies.

LinkedIn www.linkedin.com/in/stéphane-laurent-7b092211a Email [email protected]

that, the ultimate goal is to link continu-

ous API manufacturing with continuous

drug product production. Presently, in a

typical API synthetic route comprising 10

different chemical reactions, perhaps one

or two steps will be amenable to process

intensification using current technology.

There are often issues with converting

batch work-up methods — liquid/liquid

extractions, distillations, phase separa-

tions, filtrations, crystallizations, etc. — to

continuous operations. Hybrid processes

are of great interest, where conventional

and intensified technologies are com-

bined; the most important thing is to be

able to use the best chemistry, in which

case technology must not be a limitation.

Chemistry is our core business, but at

Servier CDMO we have also implement-

ed one continuous purification technol-

ogy on pilot scale: simulated moving bed

(SMB) technology. SMB is a continuous

chromatography method that enables

API purification at the level of tons per

year. This downsized equipment is cou-

pled with continuous evaporators; the

result is a reduction in the volume of

valuable stationary phases and solvents

required for separations.

In order to expand our capabilities and

work toward the goal of achieving end-to-

end continuous processing, we have ini-

tiated a collaboration with leading flow

chemistry expert Professor Steven Ley of

Cambridge University in the UK. Through

this partnership, we will be exploring the

process intensification of many differ-

ent types of chemical reactions. This is in

order to determine effective approaches to

continuous processing, which will allow us

to switch from batch mode to flow chem-

istry for a wider array of synthetic steps.

COMBINING THE BEST CHEMISTRY

AND BEST TECHNOLOGY

Expertise in flow chemistry allows Ser-

vier CDMO to provide our customers with

a combination of the best chemistry and

best technology, which translates to a sig-

nificant competitive advantage. Not every

batch reaction can be transferred to flow

chemistry, but with our ability to evaluate

the potential for process intensification

during the early phases of process devel-

opment, we are positioned to develop the

best routes using the best technology and

provide the most optimum solutions to

our customers. P


OUR CHEMICAL DEVELOPMENT EXPERTS ARE AWARE OF THE BENEFITS OF FLOW CHEMISTRY AND CONSIDER THE USE OF THIS TECHNOLOGY WHEN DESIGNING A SYNTHETIC ROUTE DURING INITIAL DEVELOPMENT.

Conceptualized bioprocess workflow and process data streams overlayed

FIGURE 1

SUT systems and the operational proce-

dures to keep operations functioning at

optimal levels.

ASSESSING OPERATIONS

The transition from process development

to manufacturing scale involves manag-

ing intensive change, typically in operat-

ing spaces (classification), layout (inter-

connected, adjacent unit operations) and

personnel (type and training level). The

efficient flow of material, personnel and

waste through the manufacturing envi-

ronment is critical to effective operations

and its ability to preserve the integrity

of the manufacturing space. Single-use

components and assemblies are involved

in most, if not all, process steps and the

volume of SUT materials introduced into


product, improve margins or make a more

competitive product. However, SUTs can

deliver a range of benefits if assessed

thoroughly before implementation. For

better outcomes, a lifecycle approach to

the assessment can help an organization

transition successfully to SUTs and realize

the benefits of the technology. Best prac-

tice puts the assessment process in front

of a cross-functional operations team to

review and understand the complete man-

ufacturing process as it relates to adopt-

ing and integrating SUTs.

A SINGULAR MINDSET

FOR SUT ASSESSMENT

Instead of looking at individual compo-

nents and assemblies, real value comes

from looking at a given process with a

broader perspective, examining opera-

tions comprehensively for interactions and

adjacencies, not only with components and

systems, but throughout operations and

with cross-functional stakeholders. Follow-

ing are key elements that can help frame an

effective assessment program and define a

sustainable single-use lifecycle for a given

process and plant setting.

VALIDATION PLANNING (QUALIFICATION,

COMMISSIONING AND VALIDATION)

To validate a given manufacturing process

and be compliant, a biopharmaceutical

manufacturer must submit to regulators

an overall master plan. This plan covers

plant, equipment, process, personnel and

documentation, including design (DQ), in-

stallation (IQ), operation (OQ) and process

qualification (PQ) elements that support

the plan. Design qualification associated

with conventional, stainless steel systems

has typically taken place prior to the con-

struction of the equipment. Single-use

technologies, however, offer the ability to

decouple some DQ activities, like material

compatibility, because SUT materials may

be prequalified. Single-use equipment

is often less complex than conventional

stainless steel counterparts. This simplic-

ity offers an opportunity to reduce the ef-

fort and time associated with IQ and OQ.

TRAINING FOR EXCELLENCE

IN SUT OPERATIONS

Compared with conventional fixed-pipe

stainless steel systems, SUTs will require

fresh training and an alignment of opera-

tions to suit the more intensive reliance

on operators for set-up, installation and

use. Bear in mind operators are not the

only functional group to be addressed.

Single-use technologies introduce a whole

new supply and inventory management as-

pect to operations, and warehouse/mate-

rial handling personnel will be impacted.

Effective training is critical to sustain-

ing the operational efficiencies associ-

ated with SUTs. New routines and training

should be introduced to address both the

mechanical and material intricacies of

> SINGLE-USE TECHNOLOGIES

Single-use technologies (SUTs) have introduced a broad range of cost and operating efficiencies to bioprocessing operations. Both in upstream and downstream, the technology offers new flexibility — but managing operations effectively can be challenging without a deeper understanding of the single-use life cycle and the effective role SUTs can play throughout biomanufacturing operations.

SINGLE-USE OPERATIONAL EXCELLENCE EXPLAINED: EFFECTIVE LIFECYCLE MANAGEMENT > BY KEN CLAPP, GE HEALTHCARE

or most of the biopharmaceuti-

cal industry, the processing of

large molecule therapeutics of

all kinds has traditionally been

tied to proprietary large-scale

stainless steel systems featur-

ing miles of stainless steel pip-

ing, fixed holding tanks, mix-

ers, bioreactors and cleaning equipment.

Although fixed systems offer their own

operational economies, especially at com-

mercial scale, biopharmaceutical manu-

facturers are seeking flexible process

solutions to help them better respond to

the changing business, product, financial

and regulatory circumstances facing the

industry today.

However, with the advent of single-use

technologies (SUTs), biopharmaceutical

manufacturers now have a viable, afford-

able path to introduce flexibility and new

operational economies into bioprocess-

ing operations.

Single-use technology is not applicable

to all molecules or bioprocess steps and,

in and of itself, will not assure a better

F

CELLS IN CULTURE

CLARIFICATION

CAPTURE PCC

VIRAL INACTIVATION

POLISHING STP OR PCC

ULTRA FILTRATION

PROTEIN

NUTRIENTS1

2

3

4

5

6

7

8

WORKFLOW DATA

PROCESS DATA

FOR BETTER OUTCOMES, A LIFECYCLE APPROACH TO THE ASSESSMENT CAN HELP AN ORGANIZATION TRANSITION SUCCESSFULLY TO SUTs AND REALIZE THE BENEFITS OF THE TECHNOLOGY.

PCC = periodic counter-current chromatography STP = straight-through processing

Ken Clapp Senior Manager, GE Healthcare

Ken Clapp is a senior manager at GE Healthcare, focusing on applications, technology and integration. He holds a bachelor’s degree in biology with a specialization in subcellular biology and a master’s degree in biological engineering, focused on biological control systems, mathematical modeling and instrumentation. Ken has worked in a variety of roles with bioprocess equipment manufacturers, including field service, sales and marketing, applied research and development, quality assurance, automation and operations management.

LinkedIn www.linkedin.com/in/kennethclapp/ Email [email protected]


the manufacturing space is significant.

As such, staging, use and disposal of

these items are central to properly align-

ing manufacturing’s material and waste

workflows.

Institutionalized standard operating

procedures (SOPs) are necessary to for-

malize the activities and ensure a robust

manufacturing process. Within the manu-

facturing space, SOPs should include con-

tingencies for single-use component/as-

sembly replacement, or substitution, and

reinforced with training. Materials inven-

tory, transfer and record-keeping should

not be overlooked either.

DESIGN AND DOCUMENTATION

In the biomanufacturing suite, the pro-

cess train forms an integrated manufac-

turing line with all the necessary unit

operation and support equipment. Unlike

manufacturing, process development is

focused more on technical performance,

rather than equipment integration and

overall, integrated manufacturing pro-

cess operations.

Process development activities can

offer an appropriate proving ground for

specifying single-use assemblies to suit

specific unit operations. Integration, or

more specifically, the interconnection of

various adjacent unit operations that make

up the manufacturing process using single-

use assemblies, requires a thorough under-

standing of the available space and layout

as well as specifics associated with con-

nections and logistics, product transfers,

etc. At this point documentation require-

ments can also be determined for the

drugs manufacturing program.

SOURCING AND PROCUREMENT

Unless a drug maker intends to design

and manufacture single-use elements in

house, supply chain partners are required.

Finding qualifiable SUT suppliers is para-

mount and critical to secure a reliable sup-

ply. Representing the internal stakehold-

ers, the sourcing function must be able

to communicate the appropriate business

and technical requirements, externally,

to potential suppliers. Single-use system

design, unit quantities, delivery timelines

and documentation requirements are a

few of the common considerations.

Single-use technology has also in-

creased the interconnectivity of the sup-

ply chain. Supply chain transparency is

important because buyers often source

components, and semi-finished and fin-

ished assemblies, from the same lower-

tier suppliers used by other top-tier sup-

pliers within the supply chain. With a

focus on the drug manufacturing process,

it should be clear as to the state of an as-

sembly’s design: prototype versus final re-

leased version.

If any design and review steps remain,

procurement plans must reflect this uncer-

tainty. Using a supply agreement to summa-

rize/catalog and codify the quality, commer-

cial, technical and documentation aspects

of the single-use lifecycle will go a long way

toward keeping individual yet interdepen-

dent businesses aligned.

MATERIALS MANAGEMENT

Single-use systems still need to be man-

aged as capital assets. These systems also

require maintenance. Sourcing and pro-

curement managers, working with other

functional stakeholders, need to reliably

convey the organization’s requirements

about packaging, labeling, documenta-

tion, purchasing forecasts, lot size and

storage requirements. Physical handling,

including quarantine, receipt inspection,

release, warehousing, staging for manu-

facturing and incorporation into a manu-

facturing bill of materials are all discrete

elements of the single-use lifecycle.

Inspection prior to manufacturing

should make use of supplier-provided in-

formation to understand what represents

a defect, or constitutes damage. Although

it is never easy to disqualify an assembly at

this stage, it is still better than deploying it

and potentially compromising a batch.

CONTINUOUS IMPROVEMENT AHEAD

Real-time data, operator feedback and in-

put from the supply chain contribute to a

more functional, efficient single-use life-

cycle. In every aspect it is important to

consider the internal and external stake-

holders involved in the SUT continuum,

and work to promote communication

among all parties to support sound, GMP-

compliant operations and continuous im-

provement over the long term.

CONCLUSION

Single-use technologies, inclusive of com-

ponents and assemblies, have become an

effective means for many biopharmaceu-

tical manufacturers to achieve improved

product quality, greater plant utilization,

and overall operational effectiveness.

When implementing SUTs, the biophar-

maceutical industry has come to under-

stand that the greatest benefits come to

those who have analyzed their end-to-end

biomanufacturing operations comprehen-

sively and have defined a single-use lifecy-

cle best suited to their products, process

and organization. P

Evolve with flexibilityDeployment of single‑use technologies throughout your facility enables you to achieve optimal performance and efficiency. Our innovative single‑use bioprocess technologies enable you to implement systems, from cell culture to downstream purification, while providing the ability to quickly scale operations.

Apply GE single‑use solutions to expand your capabilities and accelerate your bioprocess journey.

gelifesciences.com/singleuseGE and the GE Monogram are trademarks of General Electric Company.© 2017 General Electric Company.GE Healthcare Bio‑Sciences AB, Björkgatan 30, 751 84 Uppsala, Sweden.

KA1141041017AD

KA1141041017AD_SingleUse_EvolveWithFlexibility_PrintAd.indd 1 10/4/17 11:11 AM

ABOUT THE AUTHOR

SINGLE-USE TECHNOLOGIES INTRODUCE A WHOLE NEW SUPPLY AND INVENTORY MANAGEMENT ASPECT TO OPERATIONS, AND WAREHOUSE/MATERIAL HANDLING PERSONNEL WILL BE IMPACTED.

GE Healthcare provides transformational medical technologies and services that are shaping a new age of patient care. GE Healthcare is a unit of General Electric Company. Their broad expertise in medical imaging and information technologies, medical diagnostics, patient monitoring systems, drug discovery, biopharmaceutical manufacturing technologies, performance improvement and performance solutions services help their customers to deliver better care to more people around the world at a lower cost. In addition, they partner with healthcare leaders, striving to leverage the global policy change necessary to implement a successful shift to sustainable healthcare systems.

www3.gehealthcare.com +1 866 281 7545

Amersham Pl, Little Chalfont

HP7 9NA, UK

COMPANYPROFILES


Nice Insight and the Pharma’s Almanac editorial team would like to thank all the companies participating in this quarter’s edition. The following are the profiles of the industry-leading companies that have appeared in this issue. These are companies that make it their business to energize pharma’s increasingly complex supply chain, and pursue excellence every day in support of the industry’s overall quality, health and safety goals.

Alcami is a world-class supplier of comprehensive pharmaceutical development and manufacturing services. With seven sites across the globe, Alcami’s combined capabilities include API development and manufacturing, solid-state chemistry, formulation development, analytical development and testing services, clinical and commercial finished dosage-form manufacturing (oral solid dose and parenteral), packaging and stability services.

www.alcaminow.com

+1 910 254 7000

2320 Scientific Park Drive

Wilmington, NC 28405

For over 30 years, CRB has specialized in delivering high-quality bioprocess facilities that are safe, reliable and sustainable. CRB provides services across the entire project life cycle, from conceptual design through preliminary and detailed design, construction, commissioning and validation. The company has more than 900 employees across 14 offices and hundreds of project locations around the world. CRB offers a range of services from packaging solutions, fill/finish design and aseptic processing to operations improvement solutions.

www.crbusa.com +1 816 880 9800

1251 NW Briarcliff Parkway, Suite 500

Kansas City, MO 64116

Servier CDMO provides fully integrated manufacturing and supply chain services for small molecules and drug product, from development and clinical supply up to commercial launch. Servier CDMO includes a worldwide footprint with 11 state-of-the-art facilities, a proven track record in chemical synthesis, pharmaceutical formulation, development and manufacturing, and a complete range of services offering full flexibility. Services include process and analytical development, pilot production and industrial scale production, and regulatory dossier, in collaboration with the Servier network.

www.servier-cmo.com +33 1 55 72 60 00

50 Rue Carnot

92284 Suresnes, France

Marken, the clinical subsidiary of UPS, is the only patient-centric clinical supply chain organization dedicated exclusively to the global pharmaceutical and life sciences industries, supporting over 49,000 investigator sites in more than 150 countries. With decades of experience in the logistics, transport and distribution of temperature-sensitive life-saving pharmaceuticals, clinical trial supplies and specimen collection, Marken integrates standard, specialty and hybrid solutions to extend the reach of clinical trials to even the most remote, treatment-naive geographies.

www.marken.com +1 800 627 5361

4307 Emperor Boulevard, Suite 210

Durham, NC 27703

Icagen is an integrated early-discovery partner, offering clients specialized technologies and deep scientific expertise to solve myriad challenges and optimize efficiency moving from target to lead. The process begins with druggable targets, and Icagen scientists bring exceptional experience in kinases, GPCRs, ion channels and transporters. Icagen works with clients to determine drug feasibility using computational chemistry methods. Once a target is selected, Icagen combines virtual screening, ultra-high throughput screening (uHTS), biology and medicinal chemistry to generate viable leads in an abbreviated time span.

www.icagen.com

+1 919 941 5206

4222 Emperor Boulevard, Suite 350

Durham, NC 27703

SPECIAL THANKS TO:

Almac Sciences & Arran Chemical Company

Carbogen Amcis

Catalent

Cerbios-Pharma

GE Healthcare Life Sciences

Grifols

GSK Contract Manufacturing

IPS-Integrated Project Services, LLC

Lonza

Novasep

Piramal Healthcare

UPM Pharmaceuticals

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BY GUY TIENE, NICE INSIGHT

What do you see as being the most innovative technologies introduced in 2017? Why were they important? What impacts did they have?

INNOVATIVE TECHNOLOGIES

QQn the world of drug delivery tech-nologies, a year is really a blink in time. It usually takes well over a decade for a new technology to

be adapted, be proven, and to make a difference in real medicines. Over the last couple of years however, Catal-ent has seen a couple of trends in this space. One has been the development of technologies that help improve the targeted delivery of more challenging molecules with more complex profiles. For example, 2016 has seen the first FDA approval of a non-animal derived softgel capsule with a sustained release profile. Targeted delivery of capsules with enhanced functional benefits could aid a broad array of products. Another trend is advances in in silico modeling, high-throughput screening and develop-ment techniques to shorten the process of identifying the preferred formulation and dose-form approaches for each individual molecule, ideally enhancing the targeted patients’ outcomes. Accel-erated parallel screening approaches that quickly help overcome formulation challenges, such as Catalent’s newly expanded OptiForm® Solution Suite, can help innovators optimize their mol-ecules and advance them to clinic faster, with better chances of success. Given the increasing number of recalls due to contamination by visible particulates in

parenteral drugs and the heightened concern of the FDA and other regulatory agencies, manufacturing companies will pay more attention to automation in order to improve manufacturing operation and enhance its existing quality programs — resulting in more safety products for patients.

Implementation of fully automated technologies (robotics) to manufacture injectable solutions becomes an imperative to minimize quality problems and risk of contamination.

Marga ViñesBusiness Development Manager, Contract Manufacturing, Grifols

ROUNDTABLE


uring the course of year 2017, we have seen further refinement and successful implementation of a number of groundbreak-

ing, innovative technologies in the global healthcare industry. Three technologies should be mentioned in particular:

a) Precise Genome Editing (PGE) with CRISPR/Cas9 technology

b) Novel therapeutic modalities with ASO and modRNA

c) Novel diagnostic tools with liquid biopsy/ctDNA

The CRISPR/Cas9 technology enables pre-cise engineering of DNA in plants, animals and humans. The technology has been adapted at an unprecedented pace toward applications in basic and applied bio-medical research, and is now used in more than 20 ongoing clinical trials. It is widely accepted that this technology will enable therapeutic intervention in previously non-druggable human diseases.

Significant progress has also been made in the development and clinical use of anti-sense oligonucleotides (ASO) and modi-fied RNA (modRNA) as novel therapeutic modalities, hereby complementing the existing toolbox of small molecule chemi-cal compounds and large molecule recom-binant proteins. Recent progress in clinical trials based on the improved design, deliv-ery and targeting of these agents seems to enable a cost-effective and safe alternative for the treatment of human disease.

The combination of next-generation sequencing (NGS) technologies with pow-erful bioinformatics tools for analysis (‘big data’) has enabled significant advances for blood-based diagnostics (‘liquid biopsy’). These technologies facilitate fast and reli-able detection of circulating DNA (ctDNA) from tumor cells, boost clinical trials and enable numerous other blood-based tech-nologies for genomic analysis.

Professor Tom Moody, Ph.D.VP Technology and Commercialization, Almac Sciences & Arran Chemical Company

Enzyme technology and its applications are developing at a significant pace and are becoming prevalent in many areas of drug development. At Almac we are applying enzyme technology to API development in many ways. We are also seeing increasing numbers of innovator companies with enzyme technology as a key differentiator.

Antibody-drug conjugates (ADCs) are innovative therapeutics benefiting from enzyme technology. We have been involved in the selective modification of anti-bodies and attachment of key linker-payload moieties for ADC development. Enzyme technology has the potential to be site specific and/or lower the losses of linker-payload needed to obtain the desired final product. We have also been applying [14C]-technology to ADC projects by synthesizing the linker or payload, or both, with the radioactive [14C]-center. We have used ultrasound-assisted flow apparatus to aid in fermentation production of recombinant peptides and pro-teins. Ultrasound technology can aid in the soluble expression of protein and also in the up-regulation of certain pathways for metabolite production. Applying this technology and utilizing the multidisciplinary team of radio chemists, analysts and biologists at Almac minimize time and cost for clients by eliminating the need for multiple vendors.

Dr. Lorenz Mayr Chief Technology Officer, GE Healthcare Lifesciences

Elliott Berger Vice President of Global Marketing and Strategy, Catalent Pharma Solutions

D

The market for specialized injectable medicines continues to move toward high-value products with smaller batch sizes and less campaigning, including the capability to process personalized medicine. In 2017, drug manufacturers exhibited new qualified systems capable of highly flexible, efficient and compliant fill-finish technologies to meet these challenges.

On a small scale, compact robotic fillers within aseptic isolators enable safe delivery of just a few vials of a unique drug tailored to one person. At larger scales, flexible fillers allow manufacturers to process vials, syringes and car-tridges, including lyophilized products, all on one footprint. In parallel to improv-ing equipment capability, drug manufacturers and suppliers have partnered to increase the availability of ready-to-fill components to make flexibility possible. These collaborations not only provide competitive advantage for trailblazing market leaders, but their efforts also benefit the industry at large, which can immediately utilize these advances.

The trend of isolated filling systems to be more compact and affordable, a result of the above developments, affects the future of our industry. Capital-lean manufacturers historically delaying investment upgrades in legacy facilities with traditional clean rooms will have the opportunity to upgrade to state-of-the-art processes in smaller spaces at a lower cost. Upgrade of aging facilities will ultimately benefit patients.

Paul ValeroDirector, Process Technology/Associate, IPS-Integrated Project Services, LLC

I

Among the many technologies currently showing up on the horizon, we expect that we will see advances in the following three technologies — which are going to have the biggest impact for 2018 and beyond:

3D Bioprinting Digital Health Drug Delivery

e anticipate that enzyme technol-ogy will continue

to develop rapidly. “Green” chemistry is very much at the forefront of minds within the chemical industry, and utilizing enzyme technology is becom-ing the norm rather than the exception. To this end, we are extending our selectAZymeTM platform to include over 4,000 unique enzymes from diverse biological sources, which will

Constant improvement in technologies, devices and applications for 3D printing of biocompatible materials and biological samples will enable novel applications in Pharma R&D and human therapy. We predict a huge amount of innovation in that space with the development of novel additive manufacturing technologies and novel biocompatible materials. The generation of multicellular in-vitro systems and eventually even multicellular in-vivo systems/organs will enable novel applications for drug testing and thera-peutic use, eventually even tissue repair in humans.

We predict that significant progress will be made by merging advances in the development of novel instruments, including wearable devices and novel biosensors, with the development of novel software tools/applications for data monitoring, data transfer and data analysis. We expect that the field of digital health will continue to impact all areas of pharma, from R&D to manufacturing, distribution and sales, clinical diagnostics and, ultimately, to novel applications for clinical use in humans.

We predict that further advances in delivery technologies for chemical and biological molecules will enable novel applications in humans, animals and plants. This will accelerate further the use of novel therapeutic agents, such as ASO and modRNA, complex chemical molecules, novel biological molecules and formats and various combinations thereof.

be ready for immediate imple-mentation at kilogram to tonne scale. We know what our clients need, and how to deliver successfully using the most innovative techniques.

Within Arran Chemical Company (acquired by Almac in 2015), we have completed the first phase of our “ADAPT” strategy. ADAPT (Arran Deploys Advanced Production Technologies) takes innovative enzyme technologies, which would traditionally require signifi-cant process development effort prior to deployment, to an optimized state

where they can be quickly implemented in routine production, thereby meeting the challenging supply chain timeline requirements of pharma clients. Future growth at Arran will be achieved by lever-aging the power of technology, especially biotransformations. The enzyme process has proven to increase process scalability and lower cost of goods, which is a win-win for our customers.

QQ Looking forward, what technologies do you anticipate having the greatest impact in 2018?

INNOVATIVE TECHNOLOGIES

Pharma companies are increasingly looking for improved deliv-ery technologies that have the ability to deliver difficult mole-cules in a more patient-friendly way, and it is anticipated that this trend will continue.

Intelligent formulation and dose design will be even more critical earlier in the drug devel-opment process. For example, we consider that the demand for noninvasive delivery of biologics should continue to make progress. Oral delivery of peptides through technolo-gies such as Catalent’s patented OptiGel™ BIO and Zydis® BIO technologies are advanc-ing, as well as other technologies, including micro-needle arrays. Demand for treatments that patients can self-administer will also pick up speed, for example, with auto-injectors and [e-enabled] inhalers.

Professor Tom Moody, Ph.D.VP Technology and Commercialization, Almac Sciences & Arran Chemical Company

Marga ViñesBusiness Development Manager, Contract Manufacturing, Grifols

ROUNDTABLE


Elliott Berger Vice President of Global Marketing and Strategy, Catalent Pharma Solutions

Over the next coming years, parenteral packaging will experience significant changes, with a high demand for ready-to-use containers (premixed) in-front admixtures.

The main and most important concern for premixed bags is the integrity of the drug, and how to avoid any kind of interaction between plastic and drug. Technologies required to manufacture premixed bags are focused on the efficiency of filling/closing operations, high-quality requirements, fully automated fill/finish process and particles control.

Jim NadlonekDirector, Aseptic Processing Technologies, IPS-Integrated Project Services, LLC

Dr. Lorenz Mayr Chief Technology Officer, GE Healthcare Lifesciences

I n 2018, robotics will have the larg-est impact in the industry, where we’ll see high-speed lines incorpo-rate robotics to eliminate gloves in

the isolator. For any isolator, the biggest challenge today remains the gloves. Large traditional isolators with multiple lyophiliz-ers can have up to 40-50 gloves. The cost to replace gloves, the time it takes to test their integrity (whether this is visual or automated), along with the time-consuming microbial monitoring process, greatly impact the isolator turnaround time and are highly scrutinized by the quality and regulatory bodies focusing on the handling of the gloves. With a gloveless isolator, all of these issues go away.

The challenge to this is how you replace the function of “hands” in the isolator. Here’s where the use of master-slave robotic arms comes into play. Robots will replace the environmental monitoring program inside the isolator. The automatic decontamina-tion cycles within an isolator are certainly better than manual sanitization. These decontamination cycles are also very close to sterilizing all of the surfaces. One has to ask, as we approach sterilization within the isolator, can we also achieve parametric release? Hypothetically, one could equate it to filling inside an autoclave after a steriliza-tion cycle.

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